Progress in Biophysics and Molecular Biology xxx (xxxx) xxx

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Progress in Biophysics and Molecular Biology

journal homepage: www.elsevier.com/locate/pbiomolbio

Cell theory, intrinsically disordered proteins, and the physics of the

origin of life
Vladimir V. Matveev
Laboratory of Cell Physiology, Institute of Cytology, Russian Academy of Sciences, Tikhoretsky Ave 4, St. Petersburg, 194064, Russia

a r t i c l e i n f o a b s t r a c t

Article history: Cell theory, as formulated by Theodor Schwann in 1839, introduced the idea that the cell is the main
Received 8 March 2019 structural unit of living nature. Later, in solving the problem of cell multiplication, Rudolf Virchow
Received in revised form expanded the cell theory with a postulate: all cells only arise from pre-existing cells. But what did the
1 April 2019
very first cell arise from? This paper proposes extending the Virchow's law by the assumption that
Accepted 5 April 2019
between the nonliving protocell and the first living cell the continuity of fundamental physical properties
Available online xxx
(the principle of invariance of physical properties) is preserved. The protocell is understood here as a cell-
shaped physical system on the basis of the self-organized biologically significant prebiotic macromole-
Keywords:
Intrinsically disordered proteins
cules, primarily peptides, having a potential to transform into the living cell. Biophase is considered as
Proteinoids the physical basis of the membraneless protocell, the internal environment of which is separated from
Protocell the external environment due to the phase of adsorbed water. The evidence is given that the first pro-
Thermodynamic phase tocells may have been formed on the basis of intrinsically disordered peptides. Data on the similarity of
Aqueous phase the physical properties of living cells and the following model systems are given: protein and artificial
Adsorption polymer solutions, coacervate droplets, and ion-exchange resin granules. Available data on the similarity
Solute distribution of the physical properties of cell models and living cells allow us to rephrase the Virchow's postulate as
Coacervate
follows: the physical properties of a living cell could only arise from pre-existing physical properties of
Microsphere
the protocell.
Cell theory
Origin of life © 2019 Elsevier Ltd. All rights reserved.

Contents

1. Extension of cell theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

2. Membraneless aqueous phase as the physical basis of the protocell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Experimental detection of aqueous phases in cells and cell models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. The role of hydrogen bonds in the formation of aqueous phases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1. Similarities between proteinoids and intrinsically disordered proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2. Intrinsically disordered proteins as potential phasers of life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Intrinsically disordered proteins as the physical basis of the biophase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6. Functioning of the protocell as a cyclic transition between two states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7. Energy for the protocell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Declaration of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

E-mail address: vladimir.matveev@gmail.com.

https://doi.org/10.1016/j.pbiomolbio.2019.04.001
0079-6107/© 2019 Elsevier Ltd. All rights reserved.

Please cite this article as: Matveev, V.V., Cell theory, intrinsically disordered proteins, and the physics of the origin of life, Progress in Biophysics
and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.04.001
2 V.V. Matveev / Progress in Biophysics and Molecular Biology xxx (xxxx) xxx
1. Extension of cell theory
Sixteen years after Theodor Schwann's introduction of cell
theory in 1855, Virchow made an important addition to it regarding
the formation of new cells (see Wolpert, 1995 for details), which
can be summarized as “Omnis cellula e cellula” (“All cells only arise
from pre-existing cells”). This idea of Virchow's quickly gained
recognition as one of the fundamental tenets of cell theory
explaining the origin of cells. For its being flawless alignment with
the available facts, Virchow's idea is widely regarded as a postulate,
an axiom or a biological law.
Rudolf Virchow (1821-1902)
Cell theory, inclusive of Virchow's addition, has throughout its
history served as a criterion of truth in resolving many of the issues
in cell biology (Sekere
s and Z
a
rský, 2018). The only area in which
Virchow's postulate has failed to find application as a guiding
principle is the issue of the origin of the living cell. What we need to
ask ourselves here is the following: Did the first cell originate from
a cell or from something else which has nothing to do with cell
organization (i.e., in violation of Virchow's law)? The way I see it,
Virchow's postulate has only been getting more tenable over the
decades, so attempts to gainsay its applicability to the issue of the
origin of life can only be viewed as reckless. I tend to the following
opinion: for decades the Virchow's postulate only strengthened,
there is no reason to reject its applicability to the problem of the
origin of life.
In the context of the issue of life's origins, Virchow's idea may be
paraphrased as follows: Every living cell comes from a pre-existing
cell that was originally in the form of a protocell. In this paper, I am
going to make a case for the view that my interpretation of
Virchow's postulate is valid and that applying it to the issue of the
origin of life (he had nothing to say on this matter) may point the
way to new experimental and theoretical approaches.
Virchow's law, as now being applied to the issue of the origin of
Please cite this article as: Matveev, V.V., Cell theory, intrinsically disordered proteins, and the physics of the origin of life, Progress in Biophysics
and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.04.001
life, requires an answer to the following crucial question: What
does a “protocell” have that makes it possible to be a credible
forerunner to the living cell? In my view, we should look for the
development that can better be explained in how things proceeded
in terms of physics rather than rely on a biological scenario. Rele-
vant experimental data required for this are available; we currently
know of four fundamental physical properties of the living cell
(Ling, 1984, p. xxix, xxx): semipermeability, ability to selectively
accumulate certain substances and remove others from its internal
environment, ability to electric potentials, and capacity for osmotic
stability. These properties had to have been acquired by any pro-
tocell, follow which for a cell, as we know one today, could have
emerged. It turns out that Fox's proteinoid microspheres (Fox et al.,
1959), the best investigated of all protocell models, possess 3 of the
above properties, except for semipermeability (Matveev, 2017),
which simply remains to be properly researched in depth, albeit
one can confidently assume that microspheres do have this prop-
erty, as semipermeability is inherent in another model of protocell
d coacervates (see below).
As regards vesicular (membrane-based) models of the protocell,
the literature seems to be largely silent on whether or not they
possess the above fundamental physical properties. This gap can be
explained by these properties, as per the commonly held belief, is
not just a lipid film, but a full-functional membrane with complex
protein molecules that are incorporated into the lipid layer
(Nicolson, 2014). From this perspective, vesicular protocells d no
matter how many lipids they may contain d cannot have the same
physical properties as living cells without pumps, carriers, and ion
channels. Consequently, based on the expanded understanding of
Virchow's dictum followed herein, a living cell could not have
originated from a pure lipid membrane compartment, as there is a
violation of the requirement of invariability of physical properties
in a protocell being transformed into a cell. In accordance with the
adopted view, life cannot originate in a cell-like system where the
physical nature (determined by lipid membrane) is substantially
different from the physical properties of the living cell (determined
by lipid membranes with membrane proteins), and therefore ve-
sicular protocell could not have been the true precursor.
Protocells will be viewed herein as phase membraneless com-
partments, which is backed up by data suggesting that Fox's pro-
tocells and coacervates do not contain lipids, and thus do not have a
lipid membrane. The integrity of these protocells is ensured not
necessarily by an outer membrane (as a physical shell), but by
physical interactions which keep macromolecules and other key
components part of supramolecular organization, whose physical
nature is defined by the term “thermodynamic phase” (see below).
Thus, from the standpoint of cell theory, a key condition for the
origin of life is the following: physical phenomena and processes
inherent emerged in a protocell that possessed many of the phys-
ical properties seen in modern cells, i.e. from a physical point of
view there were very few if any options. The evolutionary shift from
the protocell to the living cell was possible thanks to the funda-
mental physical properties of the former and the descendant being
identical in its basic mode of operation (the principal of invariance).
Life as a protocell originated under similar physical conditions to
those which exist today. Consequently, the scientific program for
resolving the issue of the origin of life must be aimed at the search
for cell models that possess the appropriate physical properties and
in a comparative study of those properties in cells and cell models.
If we follow Virchow's dictum along the lines adopted here, we
cannot view a number of mineral substrates and geological for-
mations (e.g., sand beaches, clay, pores in minerals, warm ponds
and lagoons, geysers, etc.) as the forerunner of the living cell, as we
cannot apply to them the tenet about the unity of the above-
mentioned 4 physical properties of a cell. Geological formations can
 V.V. Matveev / Progress in Biophysics and Molecular Biology xxx (xxxx) xxx
serve only as chemical reactors on which or through which pro-
duction of compounds required for the origin of life might have
relied at some early stage.
This article is not a literature review. Its purpose is to set forth
principles that I personally find are useful for studying the problem
of the origin of life.
2. Membraneless aqueous phase as the physical basis of the
protocell
The literature indicates that research into the origin of life is
currently divided between 2 main competing areas aimed at
explaining the fundamental physical properties of the protocell: (1)
the bearer of these properties is the membrane (the standard
model; Deamer, 2016); (2) the physical properties of the protocell
are governed by its phase nature (the phase-based model or the
phase model; Matveev, 2017).
Phase-based (just like membrane-based) notions of cell orga-
nization emerged back in the 19th century (see Ling, 2007), but
were subsequently dropped due to the success of the standard,
membrane-centric, model. However, in recent years the thermo-
dynamic phase, as the physical state of the cell's substance (the
phase-centric model), has regained interest in the form of intra-cell
membraneless compartments, which emerge as a result of intrin-
sically disordered proteins (Vekilov, 2011; Mitrea and Kriwacki,
2016). A key factor for compartmentalization in this context is the
ability of certain proteins to form associates (coacervates), which
are not just a cluster of macromolecules, but the source of a new
physical reality within them. In physics, this reality is known as a
phase. Elementary example of phases that border each other would
be the 2-phase systems, ice/water and oil/water. A simple criterion
that permits calling a certain formation a phase is its immiscibility
with the environment, despite the absence of any membranes that
could impede this blending.
The physical differences between phases that are part of a 2-
phase system (e.g., cell/environment) are the cause of uneven dis-
tribution of substances between phases (discussed below), whereas
changes in a phase's properties (e.g., those caused by external in-
fluences) change the distribution of substances. From a physical
point of view, if a cell consists of phases, then it itself is a phase too.
There is plenty of experimental data, provided both as part of a
project directed by Nasonov and Troshin (Nasonov, 1962; Troshin,
1966; see Matveev, 2005) and a separate set of studies by inde-
pendent researchers (Ling, 1962, 2006; Ernst, 1963), both of their
favor the phase-based nature of living cells.
For instance, the phase-based properties of cells and models can
be encountered in investigating the distribution of solutes between
the water of the system in question and the water of the environ-
ment under conditions of diffusion equilibrium. If the equilibrium
concentration of the substance in the compartment's water is not
equal to that in bulk water, the compartment's water must be
different in its properties from regular water not affected by mac-
romolecules. Meticulous research has helped establish that the
water of living cells and cell models has less dissolving power
compared with the water of the environment d ergo, the cell/
environment and model/environment systems take on the essen-
tial attributes of a 2-phase system.
The lack of ideas on the causes of the emergence of water with
these special properties in cells has resulted in a variety of names
for it: colloidal water, bio-water, and bound (vicinal) water. A sig-
nificant drawback of these concepts is that they in no way point to
the how bio-water originated from ordinary water d and, worse,
they are leading to a number of misleading claims, even hoaxes. To
help fill this gap, I will use here, as a first approximation, a well-
known physical phenomenon such as adsorption, and use the
Please cite this article as: Matveev, V.V., Cell theory, intrinsically disordered proteins, and the physics of the origin of life, Progress in Biophysics
and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.04.001
3
term “adsorbed water” instead of the more dubious “bound water”.
The advantage of the sorption approach to explain the physical
nature of aqueous phases with reduced dissolving power is that it
helps translate the analysis of 2-phase aqueous systems into a
familiar terms and concepts, like adsorbents, adsorption sites, ad-
sorbates, structure of the surface of an adsorbent, structure of the
adsorption layer, electrostatic interaction, polarization, poly-
molecular adsorption (when the previous layer of an adsorbate is
an adsorbent for the next one), and cooperative interactions of an
adsorbate inside the adsorption layer and between layers (Dash,
1975). The adsorption of water by biopolymers is a physical phe-
nomenon that arises wherever there is water and biopolymers d
from solutions in a test-tube to cells.
Let us go back to the 2-phase system of ice/water. In this context,
phases are different aggregate states of water, which makes phase
identification a simple task. However, the phase is a broader
concept d distinct phases may also exist within a given aggregate
state of matter (Landau et al., 1967, p. 197). Ergo, similar to other
physical systems, a cell can also be multi-phase. Hence, we can ask
which component determines the phase state of a cell and its
parts? According to statistical mechanics, a system's aggregate/
phase state is determined by particles which are the greatest in
number in its constitution. For instance, the solid aggregate state of
water (ice) is determined by water, not admixtures. In a living cell,
the water concentration is ~44 М, e.g., the water content in the calf
muscle of Rana temporaria is 84% (Belton and Packer, 1974, Table 2).
If we admit that the intercellular space in a frog's skeletal muscle is
~9% of the muscle's volume (Ling and Walton, 1975), the intracel-
lular water content will be 75% (an intracellular water concentra-
tion of ~42 M).
Let us now compare this amount of water with the amount of
proteins. Half of the muscle protein composition is myosin, a pro-
tein with a molecular weight of 500 KDa (Ba r
any and Barany, 1977),
i.e., a myosin molecule is 28,000 times heavier than a water
molecule. Clearly, the myosin/water molar ratio will be negligible.
The molar contribution of other proteins to the cellular molecular
pool, except for myosin, is also really negligible, as their molecular
weight is also incommensurably greater than that of water. Ergo,
the phase properties of a living cell are, specifically, determined by
water, whose physical state changes as a result of its interaction
with different proteins (of the very many sorts) inside cells. From a
physical standpoint, the macromolecules are the adsorbents of
water (they limit its freedom of movement) not just in a cell, but in
model systems since they have a well-developed molecular sur-
face(s). The greater their molecular weight, the more effectively
they act, as is the case of linear polymers (Dobry and Boyer-
Kawenoki, 1947). On the other hand, low molecular-weight hy-
drophilic substances, e.g. sucrose, physiologically have no signifi-
cant phase-forming properties.
An elementary attribute in which 2 aqueous phases can differ
from each other is their different powers of dissolving substances.
An illustrative example of this is the 2-phase system ice/water: a
substance added to the water will not dissolve in the ice. Obviously,
water's dissolving power is determined by interactions among its
molecules, to which hydrogen bonds are the principal contributors
(Arunan et al., 2011). To dissolve, a molecule needs to break a
certain number of hydrogen bonds between the solvent's mole-
cules in order to settle into the available space. The stronger the
hydrogen bonds, the more energy needs to be expended to break
them, and the worse the water's dissolving power. Hydrogen bonds
are so strong in ice that its dissolving power falls virtually to zero
compared to liquid water. This difference is the basis for the freeze-
out effect, which implies a method for clearing water whereby with
the formation of ice-crystals the solutes are extruded from the
volume occupied by the ice-crystals into the liquid water (salt
4 V.V. Matveev / Progress in Biophysics and Molecular Biology xxx (xxxx) xxx
becomes ever more concentrated here as the ice separates from it).
Data on the phase nature of living cells will be discussed, its
properties being examined in comparison with the corresponding
properties of model systems, as is required by the proto-
physiological methodology I have already proposed (Matveev,
2017). For convenience, the term “phaser” (derived from “phase-
maker”) will be used to denote any macromolecule capable of
polarizing water (see below) and adsorbing it, which involves the
formation of an aqueous phase with stronger hydrogen bonds
(relative to bulk water) around the macromolecule.
3. Experimental detection of aqueous phases in cells and cell
models
Let us now ask how we can possibly ascertain experimentally
the existence in the system under examination of a phase of water
with reduced dissolving power. For this, we need a method that will
enable us to directly measure the solubility of substances in water,
which is equilibrium dialysis. The gist of the method is as follows. A
polymer solution is put into a dialysis bag made of a (cellulose-
based) membrane permeable to all dissolved substances except
macromolecules, and into the bathing solution a low molecular-
weight substance is introduced whose distribution we now need
to determine. After the substance is added, diffusion currents will
emerge between the dialysis bag and the environment of the
substance under examination, and water, ions, and other minor
molecules, a diffusion equilibrium will be established of all of the
system's low molecular-weight components to which the mem-
brane is permeable. If we correlate (divide) the equilibrium con-
centration of the substance under study in the water of the dialysis
bag with (by) its concentration in the water of the environment, the
coefficient of distribution of that solute in the water/water system
will be obtained, which will be a quantitative measure of differ-
ences in the dissolving power of the water in the dialysis bag and
the water outside it. If the distribution coefficient equals 1, it means
that the physical state of the water in both parts of the system is the
same. However, and in contrast, if it is < 1, we will be dealing with a
2-phase aqueous system because the water in the dialysis bag has
less dissolving power than the bulk water in the environment (see
Table 1).
Determination of the coefficient of distribution of a substance in
a 2-phase system needs meet the following conditions: the system
is in a state of equilibrium; the solvent in both parts of the system is
saturated with the substance under study; the form of the sub-
stance in both solvents must be the same (e.g., neutral). Provided
these conditions are met, the chemical potential of the substance
under study will be the same in both phases.
Table 1 lists distribution coefficients for 32 uncharged low-
molecular-weight compounds arranged in increasing molecular
weight. For comparison with the dissolving capacity of bulk water,
water was investigated in the following systems: (1) polymer so-
lutions (native hemoglobin and denatured hemoglobin, gelatin,
and polyethylene oxide); (2) membraneless compartments (coac-
ervate droplets and granules of Dowex 50 ion-exchange resin) d
n.b. the literature offers no data on Fox's microspheres in this
context; (3) living cells, e.g. muscle fibers in the skeletal muscles of
2 frog species. The data from Table 1 was used to generate relevant
graphs (Fig. 1).
According to Fig. 1, the dissolving power of water is reduced in 7
of the 8 cases, and the larger the molecule of the substance, the less
it dissolves in the water (the semipermeability phenomenon). The
only exception to this pattern is the native hemoglobin solution.
Comparing 2 hemoglobin preparations will help to figure out the
reasons that underlie the differences between them.
Native hemoglobin is a globular protein characterized by 70% of
Please cite this article as: Matveev, V.V., Cell theory, intrinsically disordered proteins, and the physics of the origin of life, Progress in Biophysics
and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.04.001
its amino-acid residues being a-helices (Vodr a
zka et al., 1972). In
the alkaline environment, a-helices are destroyed (Bhomia et al.,
2016), and the polypeptide backbone of hemoglobin becomes
accessible to the solvent. Consequently, when the helices unwind,
the number of peptide bonds accessible to the water increases,
which results in an increase in adsorbed water. Thus, denatured
hemoglobin has a larger surface for interaction with water and,
therefore, changes the nature of the increased water layer, turning
it into a phaser.
Data on polymer solutions (PEO, denatured hemoglobin and
gelatin) are direct experimental testimony to the significance of the
polymer chain coming into direct contact along the entire length of
the molecule with water to ensure the effective formation of an
aqueous phase with reduced dissolving power. Indeed, all the ox-
ygen atoms in PEO, a polymer with a linear conformation, are
accessible to water (Kjellander and Florin, 1981), whereas gelatin
molecules have a random coil conformation, i.e. they are devoid of
secondary structures at temperatures higher than that at which it
melts (Guo et al., 2003). Therefore, all peptide bonds of this protein
are accessible to water, just like peptide bonds in denatured he-
moglobin. Gelatin's fully unfolded conformation also explains the
reduced dissolving power of water in another model system, i.e.
coacervate droplets, whose phase properties have been described
at a relatively high temperature (Table 1).
Another membraneless compartment besides coacervates is
water-saturated granules of Dowex 50 ion-exchange resin (Fig. 1),
which measure between 0.3 and 0.9 mm in diameter in the dry
state. This resin is a material formed of densely packed molecules of
sodium polystyrene sulfonate, composed of crosslinks to form a 3-
dimensional network of macromolecules with a high density of
fixed negative charges. Molecules in this polymer have a linear
conformation (Marinsky, 1983), which means that all polar groups
of Dowex 50 resin are accessible to water. Thus, all of the phaser-
based models listed in Fig. 1, regardless of whether they are
macromolecular solutions (in dialysis bags) or membraneless co-
acervates and wet granules, are phases of the physical state of water
which differ from its physical state in the environment. That is,
these are 2-phase systems with an uneven distribution of minor
molecules which is not due to the properties of the membrane, but
to differences in water's properties inside and outside the
compartment.
Based on the adopted view, living cells are phase systems, as the
dissolving power of intracellular water is much less than that of the
surrounding physiological solution (Fig. 1). The substantial simi-
larity between the phase properties of living cells and models is
quite obvious, a similarity that has got to be associated with only
one thing, viz a common physical mechanism that determines the
uneven distribution of substances between living and non-living
systems and the environment, essentially the presence of water
with reduced dissolving power.
If water's properties can be changed by phasers in model sys-
tems, then there has to be phasers in living cells. Since proteins are
prevalent macromolecules in the muscle cell (and hence in all living
cells), we should above all be looking for intracellular phasers
among them. Phaser proteins, as is now apparent, do not (ideally)
contain secondary structures, and their peptide backbones must be
accessible to water along the entire length of the molecule. More
complex proteins, along with fragments that have the properties of
phasers, may contain both secondary structures and globular do-
mains (which possess no physiologically significant phase-forming
capacity). No matter what molecular basis protein phasers (pro-
teins with a linear conformation or intrinsically disordered pro-
teins, or intrinsically disordered regions of proteins) may have, in
any case functional groups of their peptide bonds are open to
interaction with water molecules. As demonstrated below, this
 V.V. Matveev / Progress in Biophysics and Molecular Biology xxx (xxxx) xxx 5

Table 1
Equilibrium distribution coefficients (q) of solutes between the systems under examination (solutions of macromolecules, coacervates, and living cells), on the one hand, and
the bathing solution, on the other, depending on their molecular weight. q ¼ Cc/Cs, where Cc, concentration of the solute in the dialysis bag (or some another system) calculated
per volume of water (mM); Cs, concentration of the same solute in the medium (mM).

Solute MW q-Value

n-Hem d-Hem PEO Gelatin Coacervates Dowex 50 Muscle T Muscle P

Methanol 32.04 e e e 0.94 e 0.61 e 0.91

Ethanol 46.07 e e e 0.91 e e e 0.81
Acetamide 59.07 e e e e e e e 1
Urea 60.06 e e e e e e e 1.05
Isopropanol 60.1 e e e 0.91 e e e e
n-Propanol 60.1 e e e 0.93 e e e e
Ethylene glycol 62.07 0.998 0.998 0.949 0.87 e 0.67 e 1.02
n-Butanol 74.12 e e e 0.91 e e e e
Tert-Butanol 74.12 e e e 0.91 e e e e
1,2-Propanediol 76.09 e e e 0.89 e e e 0.834
DMSO 78.13 e e e e e e e 0.72
1,2-Butanediol 90.12 e e e e e e e 0.87
2,3-Butanediol 90.12 e e e 0.89 e e e e
Glycerol 92.09 0.958 0.887 0.909 0.9 e 0.49 e 1
3-Chloro-1,2-Propanediol 110.54 e e e e e e e 0.893
Pinacol 118.17 e e e 0.86 e e e e
Erythritol 122.12 1.053 0.856 0.92 e e e e 0.29
D-Arabinose 150.13 e e 0.861 e e e e 0.27
D-Ribose 150.13 e e e e e e e 0.26
D-Xylose 150.13 0.98 e 0.864 e e e e e
L-Arabinose 150.13 e e e e e e 0.46 0.27
L-Xylose 150.13 e e e e e e e 0.26
Xylitol 152.15 0.936 0.837 e e e e e 0.22
D-Fructose 180.16 e e e 0.95 e e e e
D-Glucose 180.16 e e 0.879 0.94 e 0.22 e 0.227
L-Galactose 180.16 e e e e 0.61 e 0.36 e
D-Mannitol 182.17 0.961 e 0.82 e e e e 0.217
D-Sorbitol 182.17 1.035 0.84 e e e e e 0.227
D-Trehalose 342.3 0.997 0.713 0.87 e e e e e
Lactose 342.3 e e e e e e e e
Sucrose 342.3 0.976 0.627 0.768 0.77 0.60 0.24 0.28 0.132
D-Raffinose 594.51 0.971 0.552 e 0.62 e e e 0.1

MW: molecular weight; n-Hem: native bovine hemoglobin solution (39%) initially containing 0.4 M NaCl as well as the bathing solution at 25  C (the same NaCl solution was
used in the case of PEO, gelatin and Dowex 50); d-Hem: NaOH-denatured bovine hemoglobin (20%); dialysis was carried out in an alkaline solution initially containing 0.4 M
NaOH as well as the bathing solution at 25  C; PEO: poly (ethylene oxide; 15%) at 25  C; gelatin at 38  C (18%); coacervates: gelatin-gum arabic complex at 40  C; Dowex 50:
cation (sulfonate) exchange resin, spherical material of 20e50 mesh at 25  C; muscle T - frog calf muscle (Rana temporaria) at 18e20  C; muscle P: frog sartorius muscle (Rana
pipiens) at 0  C.
References. Columns from n-Hem to Gelatin (Ling and Hu, 1988; Ling et al., 1993); coacervates (Troshin, 1966, Table 104); Dowex 50 (Ling, 1965); muscle T (Troshin, 1966,
Table 22, there were taken minimal q-values because of data of Figs. 2 and 3); muscle P (Ling et al., 1993).

interaction polarizes water molecules, their dipole moment in-

Fig. 1. Dependence of the coefficient of equilibrium distribution (q-Value) of different
substances between the water of model systems and living cells and the bulk water
(the bathing solution) on their molecular weight. Based on data from Table 1.
creases, and, as a consequence, there is an increase in the power of
interaction through hydrogen bonds between them, which leads to
reduced mobility of particular molecules. These changes are a sign
of a new physical state of water that arises under the influence of
the macromolecule. A consequence of these changes is a decline in
the dissolving power of water, i.e. it tends to exclude more solutes.
Apparently, quantitative differences between the phase systems
listed in Fig. 1 are, above all, determined by (1) the chemical nature
of phasers, (2) the physical properties of functional groups of
macromolecules interacting with water, (3) the spatial distribution
of fixed charges, which governs the degree to which fixed charges
match the grid of charges in adsorbed water (e.g., the distance
between the fixed charges of the macromolecule can be equal to or
a multiple of the distance between the nodes of the network of
hydrogen bonds), (4) the distance between macromolecules, which
depends on their number in a unit of volume. Adequate quantita-
tive (and even qualitative) analysis of the above factors remains
largely an unresolved issue in physics. Let us examine just some of
the consistent patterns known to us at the moment.
The influence of the polymer concentration on the distribution
of sodium citrate between 2 water phases is shown in Fig. 2. When
the phaser concentration increases (as the macromolecules come
close to each other), water's dissolving power declines.

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6 V.V. Matveev / Progress in Biophysics and Molecular Biology xxx (xxxx) xxx
Fig. 2. Equilibrium distribution coefficient (q-Value) of Na citrate at different con-
centrations of polyethylene glycol (PEG, 25  C; mol. wt. 20,000), polyethylene oxide
(PEO, 25  C; mol. wt. 600,000), polyvinylpyrrolidone (PVP, 25  C; mol. wt. 360,000)
and gelatin (37  C; mol. wt. ~95,000) solutions in the bags and in the external solution
(Ling and Ochsenfeld, 1983, Figs. 2e4, 6, redrawn).
Macromolecules of different chemical natures differ from each
other in the efficiency of their interaction with water. When
comparing several polymer concentrations (recalculated in mM),
for q ¼ 0.4: 0.34, PEO; 0.94, PVP; 6.8, gelatin; 6.9, PEG, gelatin's
molar efficiency is the same as PEG's, but its molecular weight is 5
times greater. Thus, the protein's amino acid chain interacts with
water more weakly than PEG's monomer chain. A polymer's ability
to influence water's properties depends not only on its own
chemical nature, but on the length of the molecule (Fig. 3).
Apparently, this is why the longest polymer, PEO, is the most
effective phaser among those listed in Fig. 2.
It is worth taking into account a set of more complex physical
factors that can influence the properties of the adsorbed water
phase (Ling and Ochsenfeld, 1983): (1) when macromolecules come
close to each other, their aqueous shells can merge, and their
common volume can increases to a degree due to the cooperative
interactions of the water molecules; (2) the ordered positioning of
macromolecules (parallel to one another) increases the volume of
Fig. 3. Lowest polyethylene glycol concentration at which all water is bound versus
molecular weight of the polymer (Tilcock and Fisher, 1982; drawn according to data in
Table 1).
Please cite this article as: Matveev, V.V., Cell theory, intrinsically disordered proteins, and the physics of the origin of life, Progress in Biophysics
and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.04.001
adsorbed water, whereas their disordered arrangement reduces it;
(3) alternation of positive and negative charges (as in a chess-board
fashion), as is the case with a chain of peptide bonds (NHeCO), also
stabilizes the adsorbed water phase, facilitating increase in the
volume of water with reduced dissolving power. This important
characteristic of proteins was pointed out by Ling (1972). Due to the
alternation of different-polarity charges, the water molecular
interacting with NH faces the peptide chain with its negative pole,
whereas the neighboring water molecule interacting with CO faces
it with its positive pole. Thus, the two neighbor water molecules are
oriented in such a way that the positive pole of one of the molecules
is near the negative pole of the other. The electrostatic attraction of
neighboring water molecules with a reverse pole orientation
further stabilizes the water layer that is held in place by the poly-
peptide backbone of protein.
To sum up the contributions from all these factors, the more
effectively macromolecules in models and living cells reduce wa-
ter's dissolving power, the more favorable the conditions for
increasing the volume of the adsorbed aqueous phase, and the
lower the position of the curves shown in Fig. 1. In this respect,
Dowex 50 resin comes very close to living muscle, and, therefore,
can give us a general idea of the fundamental properties of phasers
in living cells. Ideally, they must be something like long and
extended molecules that are completely open to interaction with
water, with a high density of fixed charges. The excluded volume
(the volume occupied by macromolecules) plays no role in these
phenomena, as the data listed in Table 1 were obtained only for
water, no matter how little remains in the coacervate or the living
cell.
Since adsorbed water is detected in experiments that are hours
or days long, it is clear that, no matter how dynamic its structure
may be, it definitely plays a key role in the life of a cell d it divides
(separates) solutes in space. The adsorbed water phase can persist
for long periods of time, and does not dissolve in bulk water. In that
respect, it may be compared to oil in an aqueous environment. This
qualitative analogy is backed up by quantitative data.
Moving on, let us now compare the dissolving power of the
alcoholic phase of the n-octanol/water system with that of intra-
cellular water in the living muscle water 2-phase system in a
physiological solution. As an example, let us consider the data for
ribose. The distribution of this sugar in the n-octanol/water system
is characterized by the quantity q ¼ 0.0048 (Leo et al., 1971), and in
the (cell water)/(bathing water) system d q ¼ 0.26 (Table 1). In
other words, the alcohol phase dissolves ribose 208 times (1/q) less
than the aqueous phase, whereas intracellular water dissolves 3.8
times less ribose than the water in the bathing solution. The dif-
ferences are of a quantitative nature, whereas the qualitative result
is similar, i.e. the solubility of ribose in both the alcohol phase and
intracellular water is lower than in bulk water. Since octanol is a
solvent with pronounced hydrophobic properties, intracellular
water must be more hydrophobic than the bathing physiological
solution (i.e. the analogy to oil is proving true). The relative hy-
drophobicity of intracellular water can be explained by water
molecules in the adsorption layer prefer interacting with each
other, not with bulk water because of the hydrogen bonds within
the adsorption layer are stronger). For the same reason, the poly-
peptide helix is more hydrophobic than the unfolded conforma-
tion; it is more advantageous energetically for peptide bonds to
interact with each other than with water.
We should not overlook the fact that Table 1 data were obtained
by a direct method, i.e. directly determining a substance's solubility
in water. Indirect methods interpret the phenomenon under study
using mathematical, physical, or computer models, and therefore
have no evidential force. By contrast, direct methods reflect the
actual physical reality.
 V.V. Matveev / Progress in Biophysics and Molecular Biology xxx (xxxx) xxx
A comparison of the semipermeability (fundamental physical
property) of living cells and models (Fig. 1) shows that the basis of
this property is a physical mechanism common to living and
nonliving systems d a reduction of dissolving power of water. This
similarity suggests that the first living cell could inherit semi-
permeability from the protocell.
Additional notes to Table 1.
1. In all of the cases, the starting point in the study was to deter-
mine the time required to reach diffusion equilibrium. It ranged
between 5 and 24 h and 6 days for different systems. In each
experiment, the incubation time was always longer than the
corresponding time for reaching diffusion equilibrium.
2. The substance distribution coefficient (q) was determined not
for particular concentrations in the object under study and the
environment, but was based on the dependence of the con-
centration inside relative to the external concentration. Based
on the slope of the linear portion of the resulting curve, the
investigators determined the quantity q, which does not depend
on how much substance was adsorbed by the macromolecules
of the model and the living cell (Troshin, 1966, p. 86), i.e. q is a
quantitative measure of differences solely between the aqueous
phases.
3. Polymer concentrations in dialysis bags are listed as at the start,
not the end, of the experiment. This is permitted because
changes in their volume during establishment of diffusion
equilibrium were insignificant as only small concentrations of
the solutes were used for distribution analysis. For this reason,
changes in the volumes of other systems examined were also
negligible.
4. The experimenters took into account that involuntary bacterial
contamination of solutions could distort their findings. How-
ever, in most of the cases, incubation time was several hours e
too short for the development of any microflora. In the case of
frog calf muscle, the bacterial control procedure did not detect
any substantial increase in bacterial contamination within a 5-h
period (a standard time of incubation). The sartorius muscle of a
leopard frog (Rana pipiens) was incubated for 6 days at 0  C (a
tolerable temperature for this species), i.e. under conditions that
would suppress the development of any microflora.
5. At 0  C, the metabolism of leopard frog muscles was virtually
completely suppressed. Therefore, this factor would not have
distorted the experimental findings for substances that might
cause metabolic changes. Where possible, the investigators used
substances that cannot be metabolised on account of their
chemical nature (these substances were used in experiments on
the muscles of Rana temporaria frog). The qualitative similarities
in the data for both frog species attest that, in the case of Rana
pipiens, the metabolism of the muscles could not possibly cause
tangible distortions in the final result.
6. The experimenters explored the distribution of electrically
neutral molecules, and thus insignificant changes in ion distri-
bution d typical in the establishment of diffusion equilibrium -
could not affect the distribution of uncharged molecules.
4. The role of hydrogen bonds in the formation of aqueous
phases
We are going to make use of the following definition proposed
by Adkins (1983, p. 3): “Phase is defined as a system or part of a
system which is homogeneous and has definite boundaries”. In as
much as we are convinced that water with reduced dissolving
power is a phase, it must therefore have definite boundaries. It is
apparent that, on the one side, it borders on the molecular surface
Please cite this article as: Matveev, V.V., Cell theory, intrinsically disordered proteins, and the physics of the origin of life, Progress in Biophysics
and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.04.001
7
of the phaser, and on the other it does with regular (bulk) water.
Notions of water in living cells being different from bulk water
gained a foothold as far back as the 19th century. With the emer-
gence of colloid science, there was a spike in interest in water in
multi-phase systems, and later data started to appear on the role of
bound water in the functioning of a living cell. The nature of
research on bound water began to be more fully conducted in the
second half of the 20th century, as may be judged from some of the
major publications, e.g. Eisenberg and Kauzmann (1969), Franks
(1975), Clegg (1979), Hazlewood (1979), Horowitz and Paine
(1979), Trantham et al. (1984), Wheatley (1991), Agutter et al.
(2000), Drost-Hansen (2006), Tasaki (2008), Mentre  (2012), Tre-
vors and Pollack (2012), Pollack (2013) and Jaeken (2017).
The key question is ‘in what way do phasers influence the
properties of water?’ Perhaps, one of the first scholars to attempt to
answer this question was Jacobson (1955): “If the macromolecule
has many oxygen and nitrogen atoms on the surface in such posi-
tions that they fit into the ideal water lattice, a very pronounced
ordering effect is obtained and results in an almost ideal four-
coordinated structure”. Based on this supposition, the molecular
surface of a phaser must possess the following characteristics: (1)
there must be fixed charges on it (in the case of protein, these are
nitrogen and oxygen atoms in peptide bonds, side-chain carboxyl
groups of dicarboxylic amino acid residues, and side-chain groups
of arginine and lysine residues that contain nitrogen); (2) there
must be some kind of a match between the spatial positioning of
charges in the protein and that in the network of hydrogen bonds of
water to ensure effective interaction. A more complete picture of
the formation of an aqueous phase in the presence of protein was
proposed by Ling (1965, 1972, 2006). However, despite these sub-
stantial contributions, many different aspects of interaction be-
tween proteins and water remain vague even to this day.
The leading intermolecular interaction that determines the
properties of water is electrostatic in nature, which takes the form
of a hydrogen bond (Arunan et al., 2011). The more the electron
structure of the water molecule differs from its unperturbed state,
the greater its polarization, the greater its dipole moment, and the
greater the energy of the hydrogen bonds (this is fair not only for
the molecule as a whole, but for particular dipole groups of com-
plex molecules, e.g. proteins).
The dipole moment of molecules is not an invariable quantity; it
depends on electrostatic interactions with other molecules. More
specifically, in the transition from a gaseous to a liquid state in
which water molecules start interacting with each other, the dipole
moment increases 57% (from 1.85 to 2.9 D) as a result of its polar-
ization (Kemp and Gordon, 2008); however, if water interacts with
a dipole that is stronger than itself, its moment will become greater
and surpass the moment of the other water molecules in the vol-
ume. For instance, the total dipole moment of atoms in a peptide
bond is 3.5 D (Collins and Leadbeater, 2007), which is then 20%
greater than the dipole moment of water in a liquid state (2.9 D).
Based on computer modeling, the dipole moment of the alanine-
alanine dipeptide can vary from 2.9 to 11.0 D depending on the
conformation (Wang and Duan, 2004, Table 3).
The figures provided attest that the dipole moment of the
peptide chain can vary in a wide range (Eckshtain-Levi et al., 2016),
and, therefore will have a considerable polarizing effect on water.
Indeed, the dipole moment of water in the adsorption phase is 5.8 D
in some estimates and 10 D in others. This significant boost in
polarization is the result of the effect on water of electric fields on
several dipoles e from particular functional groups to the cumu-
lative dipole moment of the protein molecule jointly with the shell
of bound water (LeBard and Matyushov, 2010). Thus, the ability of
phasers to polarize water and thereby increase the energy of
hydrogen bonds becomes obvious. A general consistent pattern
8 V.V. Matveev / Progress in Biophysics and Molecular Biology xxx (xxxx) xxx
that is of special significance is that, when there is a boost in the
polarization of dipole molecules, the energy of hydrogen bonds
increases (Xu et al., 2002). Also of importance for the protocell is
the fact that the dipole moment of water and other molecules is
temperature dependent (Sokhan et al., 2015).
The range over which the energy of water's hydrogen bonds can
change is evidenced by the following data: the specific heat of
evaporation of liquid water at 0  C is 10.7 kcal/mol, whereas the
specific heat of sublimation of ice at the same temperature is
12.15 kcal/mol (Buijs and Choppin, 1963). If we accept that the
energy of a hydrogen bond is proportionate to the heat of transition
of water molecules to a gaseous state, then water will completely
lose its dissolving power at 0  C when there is only a 14% increase in
the strength of a hydrogen bond (as it turns into ice). It is clear from
general considerations that changes in the dissolving power of
liquid water under physiological conditions will be accompanied by
even smaller changes in the energy of a hydrogen bond. Based on
one estimate, the energy of a hydrogen bond in the adsorption
phase of water will be only 126 cal/mol greater than in the bulk
volume (Ling et al., 1993). No matter how small this quantity may
be, it is important for it to suffice for physiologically significant
effects. Since macromolecules differ in their quantity, quality and
topology of charged groups, they will form adsorption aqueous
phases varying in structure and strength around each other. These
differences seem necessary and sufficient for the formation in a cell
or a protocell of aqueous phases with different properties that will
have hydrogen bonds stronger than those in bulk water.
If the phaser's molecular surface polarizes water, this will also
inevitably entail the ordering of its molecules at that surface. This is
due to polar groups in the artificial polymers listed in Fig. 1 (PEO
and Dowex 50) being positioned along the polymer chain in a
strictly defined order. Thus, water molecules engaged in interaction
with them will also become ordered in space. A similar sequence of
dipole ordering will also be in the backbone of any protein.
If the first adsorption layer has an ordered structure with pos-
itive and negative charges, positioned in a chess-board fashion, the
second layer will also be ordered and, in turn, serve as an adsorbent
for the third layer, and so on, i.e. continuation of layer-by-layer
association of water around the phaser will lead to the emer-
gence of a multi-layer architecture in the adsorption phase. Since all
the water molecules in this phase are polarized, they will be linked
to each other by stronger hydrogen bonds than in the bulk water,
which will allow such a phase to stably exist in the surroundings of
bulk water. Layer-by-layer adsorption of water by macromolecules
has been gaining recognition (e.g. Meriçer et al., 2017). The coop-
erative nature of a hydrogen bond (Eisenberg and Kauzmann, 1969,
p. 257), when each subsequent water molecule augments the po-
larization of molecules within the ensemble, also facilitates the
strengthening of intermolecular hydrogen bonds in the phase. The
low velocity of the thermal motion of high-mass macromolecules
compared with low-mass ones is an additional factor for stabilizing
the adsorption layer of water because it reduces the kinetic energy
of its molecules.
A phase with stronger hydrogen bonds has on its external
border a surface tension that surpasses the surface tension in the
surrounding aqueous environment which it borders on. As a
consequence, this kind of phase will have higher surface energy,
while, as we know, the minimum specific surface energy is ach-
ieved only when the phase is spherical (e.g., a droplet of water
assuming a spherical shape in oil). The relationship between sur-
face tension and the spherical shape of droplets in the context of
aqueous phases has been described (Zwicker et al., 2017). Conse-
quently, if as a result of interaction between the macromolecule
and water from the solution there emerges a new phase, this in
itself is testimony to hydrogen bonds between water molecules
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and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.04.001
being stronger than those in the mother solution (in bulk water),
and the shape of the new phase will tend to be spherical.
The system tends to reduce specific surface energy will lead to
the fusion of aqueous phases if the surface tension in the dispersion
environment is lower (as is the case with droplets of water in oil).
The aqueous phases with high surface tension get absorbed by
phases with low surface tension (Foty and Steinberg, 2005).
The interaction of phasers with other components in the envi-
ronment, other than water (phosphates, for example), may lead to
significant changes in their sorption properties (selectivity, for
example), and as a result, to the division of a relatively homoge-
neous system into 2 or more immiscible phases, i.e. the division of
the protocell under the influence of changes in the environmental
conditions may be viewed as a phase separation. An example of this
phenomenon is the division of Fox's microspheres when there is a
change in pH (Fox and Yuyama, 1963), or the emergence of 2 phases
in an originally one-phase system when there are changes in pH
and temperature (Hamzehzadeh and Zafarani-Moattar, 2015).
Of paramount significance for the phase protocell, as the cradle
of life, is the ability of the adsorbed water phase to push out any
particles that are not integrated into the phase, including free water
molecules, molecules of organic substances, ions including Hþ,
proteins, and colloidal particles. Based on the aforesaid, the phase
nature of adsorbed water is capable of creating a concentration
gradient of virtually any substance, neutral or charged, by pushing
it out of the phase. In the event of the emergence of ion concen-
tration gradients, there will inevitably be a difference in electric
potential between the phase and the environment.
There is another mechanism for the emergence of gradients,
namely adsorption of solutes on the molecular surface of a phaser. If
the phaser is an effective adsorbent for a certain component in the
solution and can bind it in physiologically significant quantities,
that solute will be concentrated by the phaser due to the forces of
adsorption. If the substance is an ion, this will lead to the emer-
gence of a corresponding ion gradient, and hence an electric po-
tential. If, for instance, Kþ is selectively adsorbed in the presence of
Naþ, the electric potential of the protocell will essentially be due to
potassium. The ability of Fox's microspheres to accumulate
considerable amounts of Kþ is well-known (Ishima et al., 1981,
Table 1): the concentration of this cation in microspheres is 1,600
times greater than in the environment from which it was obtained.
However, it is crucial for the protocell to accumulate Kþ in the
presence of Naþ, which is prevalent in sea water. Since the proteins
of living cells possess this kind of ion selectivity (Edelmann, 2014),
it is important to find a model of the protocell with the same
properties. The role of adsorption in the operation of living cells and
model systems was investigated by the Russian school of cell
physiology over half a century ago (Troshin, 1966).
Thus, a single physical phenomenon, adsorption of water and
other physiologically important solutes, can help explain several
phenomena which, supposedly beforehand, seemed to have
nothing to do with each other: (1) semipermeability (the cause
being that the solute is excluded from the adsorption phase of
water the better, the larger its molecule); (2) the ability to selec-
tively accumulate certain solutes and exclude others (the cause
being the selectiveness of the phaser adsorption sites and the
reduced dissolving power of the sorption phase of water); (3) the
ability to generate electric potentials (the cause being the forma-
tion of ion concentration gradients as a result of selective adsorp-
tion, on the one hand, and removal of ions from the sorption phase
of water, on the other); (4) osmotic stability (the cause being the
stability of the sorption phase of water within the boundaries of
physiological changes in the osmotic pressure of the environment).
When there are changes in the sorption properties of the protein
phaser, all the above physical properties will naturally change in a
 V.V. Matveev / Progress in Biophysics and Molecular Biology xxx (xxxx) xxx
synchronous fashion because all of them are governed by one ac-
tion, namely adsorption.
As previously stated, the above 4 properties are regarded as
fundamental physical properties of a living cell. They are also found
in cell models, properties 1, 2, and 4 in coacervates (Troshin, 1966)
and 2, 3, and 4 in microspheres (Fox et al., 1970, Fig. 5; see also
Matveev, 2017). The data of Fig. 1 also indicate the fundamental
similarity of model and living cell semipermeability. Thus, with
reference to the problem of the origin of life, the extension of the
Virchow's law can be formulated as follows: the fundamental
physical properties of a living cell could only arise from the
fundamental physical properties of the protocell. While our
knowledge of the physical properties of the model is fragmentary at
this time, it can provide insight into the underlying physical
properties of living cells and conditions under which they emerged.
From the standpoint of the phase-based approach, an elemen-
tary unit of the living cell is the molecule of a phaser that is pro-
teinaceous in nature with water, ions, and other substances
adsorbed on it (Fig. 4). This ion-water-protein complex may be
termed the “physiological atom” (Matveev, 2005), “nano-
protoplasm” (Ling, 2007), or “nanobiophase”, as an elementary
further indivisible unit of the biophase, an aqueous phase based on
polypeptides (Matveev, 2017). The self-assembly of physiological
atoms leads to the formation of the protocell, i.e. to the cradle of life.
Any cell structure (membranes, organelles, cytoskeleton, etc.) may
be viewed as a composite of physiological atoms joined up to form
physiological molecules, which differ in structure and function.
Physiological atomism may be viewed as an extension of biological
atomism (Nicholson, 2010) to cell physiology.
4.1. Similarities between proteinoids and intrinsically disordered
proteins
Consider the following question d were the first proteins on
Earth phasers or globular proteins? The decisive advantage of
phaser proteins lies in the fact that a phase emerging in their
presence is an elementary compartment (only peptides and water
are needed). Due to the binding of water, there emerges inside the
phase an environment that by its physical properties differs from
the external environment, whereas to maintain these differences
there is no need for a membrane with complex structured proteins
built into it, whose spontaneous emergence has yet to be demon-
strated. On the other hand, the abiotic synthesis of short peptides
Fig. 4. Schematic illustration of a physiological atom based on a single peptide
molecule. The peptide is surrounded by an aqueous shell (the aqueous phase), which
formed on its molecular surface as a result of the multi-layer adsorption of water
molecules. Besides water, the only substances that are selectively adsorbed by the
peptide are kept inside the physiological atom (e.g., Kþ is selectively adsorbed in the
presence of Naþ, the relative dimensions of hydrated cations being shown), whereas
the rest of the ions and minor molecules (not shown) are excluded from the adsorbed
water phase into the surrounding solution. Ensembles of physiological atoms, which
form due to self-assembly, form biophases of different sizes, and all the way to the
protocell.
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and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.04.001
9
containing almost no secondary structures is beyond question (see
below). Nanobiophases, which emerged based on this kind of
peptide, form a phase protocell that becomes a reactor of specific
physical and chemical processes (which are impossible outside of
the biophase) and that could lead to the origin of life. In an attempt
to find new evidence in favor of the phase-centric hypothesis of the
origin of life, we need to compare proteinoids (Fox, 1991) with
intrinsically disordered proteins (Wright and Dyson, 2015). These
polymers appear to share a number of common features, which can
be crucial to further search for life's origins.
From the standpoint of molecular structure, proteinoids are
mainly authentic polypeptides (Fox, 1976). What makes them
interesting is that they can be obtained in conditions which, sup-
posedly, are close to those on the early Earth, whereas micro-
spheres which they spontaneously create are the best known
model of a protocell among those that have been proposed to date.
It was obvious to the first researchers of microspheres that these
formations are phases (Fox, 1976), as they do not contain lipids and
therefore no lipid membranes, but at the same time manage to
maintain their integrity.
A fundamental property of proteinoids that has been overlooked
is their self-determined (non-accidental) amino-acid composition
and primary structure (Fox, 1969, 1981, 1985, 1991, 1992;
Nakashima et al., 1977; Dose et al., 1982; Varfolomeev, 2007;
Mosqueira et al., 2012). This is attested by the differences be-
tween the composition of initial mixtures of amino acids and the
amino-acid composition of proteinoids obtained by the heating of
these mixtures. In addition, the frequency of emergence of amino
acids at the Ce and N-termini was not proportionate to the molar
fraction of the amino acid in the reaction mixture (Dose, 1974). This
means that the composition of proteinoids is not a copy of the
composition of the reaction mixture, whereas the primary struc-
ture is determined by yet unknown properties of amino acids and a
growing peptide, which for some reason tends to incorporate
certain amino acids more frequently than others. The idea of the
vitally important peptide emerging accidently is faced with insu-
perable difficulties. If that were the case, out of the immense
number of accidental peptides that formed on the surface of the
early Earth, only a few would have been of biological value
(Steinman, 1967; Tokuriki and Tawfik, 2009).
The mechanism for the self-determination of peptide compo-
sition and structure is one of the fundamental physical factors in
the origination of life. It is a sort of physical selection that preceded
biological selection, and may still to this day be playing a significant
role in life processes.
An important characteristic of proteinoids is the nearly com-
plete absence of spiral structures and a low molecular weight of
4,000e10,000 Da (Dose, 1974). The low number of secondary
structures explains the low activity and specificity of the catalytic
sites of proteinoids (Dose, 1984; Fox, 1980). The molecular weight of
most proteinoids obtained by others ranges up to 2,000 Da (Brack,
2007).
The most studied microspheres are the microspheres of acidic
proteinoids, as they are distinguished by the greatest resistance to
changes in environmental conditions and can have a storage period
of 6 months (Kolitz-Domb and Margel, 2015). Considerably less
stable are microspheres composed of basic proteinoids (Rohlfing,
1975). The molecular weight of proteinoids increases in the
following order: acidic, neutral and basic (Dose, 1974). Besides
stability, acidic proteinoids impart to microspheres the potential
ability to bind cations, which are vitally important (e.g., Kþ). It is
noteworthy that proteinoids that do not contain residues of hy-
drophobic amino acids do not form microspheres (Rohlfing, 1975),
which is testimony to the decisive role of hydrophobic interactions
in the formation of protocells.
10 V.V. Matveev / Progress in Biophysics and Molecular Biology xxx (xxxx) xxx
Based on the findings from chromatographic analysis, the resi-
dues of dicarboxylic amino acids (aspartic and glutamic) are the
main components of the best known acidic proteinoids (Fox et al.,
1963). Among the rest of the amino acids, lysine and alanine are
present in proteinoid in the greatest amount (>6 M %; Fox, 1976).
Based on other findings, the 6% threshold in the acidic proteinoid
No. 50 has been overcome by the aspartic and glutamic amino acids
(the combined content of both amino acids being 54.3%) and
alanine (6.7%). In the neutral proteinoid No. 53, the combined
content of dicarboxylic amino acids was 24.2%, whereas the 6%
threshold was exceeded by lysine (14.3), glycine (9.4), leucine (7.9),
valine (7.7), and alanine (6.3) (Fox and Waehneldt, 1968). The
amino-acid composition of the hydrolysate of the acidic proteinoid
Prot A7 (in mM) is as follows: 95.6, aspartic acid; 49.6, glutamic
acid; 30.4, glycine; 15.5, proline; 13.4, leucine; 10.7, arginine; 4.9,
tyrosine (Kumar and Rao, 1998). By their physical properties, the
amino acids present in proteinoids are distributed as follows: acid
(Asp, Glu), basic (Arg, Lys), polar (Tyr), and hydrophobic (Ala, Gly,
Leu, Pro, Val).
Although these proteinoids are obtained under different con-
ditions, the available data can give us a general idea of the amino-
acid composition of this type of phasers; they are hydrophilic
macromolecules with a large number of negative charges and a
poor amino-acid composition. This is the result of activity by an
unknown mechanism for the self-determined polymerization of
amino acids.
Let us now examine the amino-acid composition of peptides
with a natively unfolded conformation, which include (1) intrin-
sically disordered proteins, and (2) intrinsically disordered regions
of compound proteins with diverse local structures (for conve-
nience, let us join these two to form a single term, i.e. intrinsically
disordered peptide chains, IDPCs, which can both be a separate
molecule and/or form part of compound proteins).
There is a firmly entrenched view that IDPCs are rich in charged
residues, with dicarboxylic amino acids being prevalent, but having
a poor amino-acid composition (Aguzzi and Altmeyer, 2016;
Bergeron-Sandoval et al., 2016; Courchaine et al., 2016; Mitrea
and Kriwacki, 2016; Yu et al., 2016). Their similarity to proteinoids
is obvious, which gives grounds for viewing proteinoids as models
of primeval IDPCs, and IDPCs themselves as the first phaser pro-
teins, which paved the way for IDPC-microspheres or IDPC-
protocells. It remains for us to ascertain that IDPCs interact with
water, without which the emergence of the biophase is impossible.
4.2. Intrinsically disordered proteins as potential phasers of life
There has recently been significant interest in membraneless
cell organelles (Banani et al., 2017). As is clear from the name, the
integrity of these organelles is ensured not by the membrane, but
by physical interactions that result in the formation of a phase,
while IDPCs are viewed as an essential component in these aqueous
phases. However, in these studies, phase formation is not viewed as
the result of changes in the physical state of water (Shin and
Brangwynne, 2017); nevertheless, data on water's interaction
with IDPCs have been published (see below).
The interaction of IDPCs and globular proteins with water has
been investigated using various methods. The findings can be
summarized as follows.
1. IDPCs have a greater ability to bind water than globular proteins
(Bokor et al., 2005; Jose et al., 2014), including also thanks to a
high content of charged amino-acid residues (Rani and Biswas,
2015a). In addition, the molecular surface available to the sol-
vent is several times larger with IDPCs than with globular pro-
teins (Schiro et al., 2015). The unfolded polypeptide chain,
Please cite this article as: Matveev, V.V., Cell theory, intrinsically disordered proteins, and the physics of the origin of life, Progress in Biophysics
and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.04.001
which results from the denaturation of the globular protein,
interacts with water as effectively as IDPCs (Mamontov et al.,
2010).
2. The mobility of water molecules in the hydration shell around
IDPCs is lower compared with water molecules at the surface of
globular proteins (Gallat et al., 2012; Rani and Biswas, 2015b).
When the conformation rigidity of IDPCs increases, the move-
ment of water molecules in the hydration shell slows down
(Gavrilov et al., 2017).
3. Displacing the water molecule from its position in the hydration
shell of IDPCs requires 50% more energy than is the case of the
hydration layer surrounding globular proteins (Bokor et al.,
2005).
4. Carboxyl groups in peptides' side chains sharply reduce the
mobility of water molecules in their hydrate shell (Gavrilov
et al., 2017).
5. The average density of the water around IDPCs is higher than
bulk water (Rani and Biswas, 2015b). The data provided in items
2e5 attest to hydrogen bonds between water molecules in the
adsorption phase strengthening, which has been substantiated
by a relevant theoretical analysis (La bas et al., 2017). This
increased strength is ensured by the following two factors:
interaction of water molecules with a protein surface as well as
between each other (Song et al., 2014). Second, this leads to the
water around the protein being polarized and having an
increased dipole moment.
6. The free energy of the binding of water is greater in the case of
IDPCs as opposed to the globular domains of the same protein
(Awile et al., 2010). Furthermore, the strength of water/protein
binding declines in the following order: IDPCs, globular pro-
teins, membrane proteins (Gallat et al., 2012), i.e. the greater the
number of peptide bonds in secondary structures, the smaller
the amount of hydration water adsorbed by the protein (per
peptide bond). In other words, when a globular protein is de-
natured as the polypeptide chain unfolds following destruction
of secondary protein structures, the volume of adsorbed water
increases.
7. The structure of the water around IDPCs is of a more orderly
nature (Rani and Biswas, 2015b). As recently discovered, water
at the surface of a cryoprotectant protein (proteins of this family
belong to intrinsically disordered proteins; Matsuo et al., 2018)
has an ice-like structure (Meister et al., 2014), i.e. there are
certain similarities between the structure of the adsorption
phase of water and liquid crystals.
8. The degree of orderliness of the water is proportionate to the
length of IDPCs (Rani and Biswas, 2015b), a pattern attested by
the data in Fig. 3. That is, when the length of IDPCs increases, the
volume of the adsorption aqueous phase also increases, whereas
an increase in that volume leads to a more pronounced contri-
bution of the water-water interaction cooperativity factor in the
structure of the adsorption layer (Dominelli-Whiteley et al.,
2017).
Thus, the data leave no doubt that IDPCs are effective adsorbents
of water compared with globular proteins, which is a necessary
condition for the formation of aqueous phases.
Now consider the following questions: How many layers of
water can there be in the aqueous shell around IDPCs? Is the
adsorption phase a multi-layer? As a result of the polarization of
water molecules induced by the polar groups of proteins, the
aqueous shell around e.g. insulin consists of no fewer than 5 layers
bas et al., 2017). Since insulin is a globular, there is
of water (La
reason to expect that the aqueous shell around peptides with an
unfolded conformation, which interact with water better, will
contain more 5 layers. Indeed, the thickness of the aqueous shell
 V.V. Matveev / Progress in Biophysics and Molecular Biology xxx (xxxx) xxx
around linear peptides can be over 20 Å (Gavrilov et al., 2017). If we
admit that the thickness of one aqueous layer is approximately
equal to the diameter of a spherical water molecule (2.8 Å, D'Arrigo,
1978), the estimate would be 7 layers of water. However, on the
mineral sorbent, the thickness of one layer of water is established at
1 Å (Ganta et al., 2014), which means that a spherical shape is a
rude approximation, while the thickness of the adsorption layer
depends on how water molecules are oriented in relation to each
other and to the sorbent. Since the conformation of IDPCs is dy-
namic, it is apparent that the number of layers of water in the
adsorption phase may range widely depending not only on the
conformation, but on the dipole moments of particular fixed
charges and the macromolecule as a whole.
When the concentration of macromolecules is increased, the
aqueous shells of neighboring phasers can unite, in which case the
thickness of the adsorption aqueous phase will now be 30e40 Å,
whereas the dynamics of water molecules in the aperture between
the 2 macromolecules will be a lot slower than in bulk water
(Gavrilov et al., 2017). In the case of the phaser protein, gS-crys-
talline, the dynamics of the hydration water will be nearly twice
slower than that of bulk water; it is worth noting that it does not
depend on protein concentration up to ~550 mg/ml. This means
that water properties are determined by the characteristics of its
diffusion near the surface of the protein (Huang et al., 2016), not by
the mechanical capture of the water by the network of protein
molecules, as normally thought to be the case with hydrogels.
The hydration layer around gS-crystalline cannot only be thick,
but firm, stable and strong to a sufficient extent to hinder protein-
protein interactions (Gavrilov et al., 2017).
It has been estimated that due to the close positioning of pro-
teins to each other in living cells (crowding), 5e6 layers of water
will suffice for 90% of the water within a frog's muscle fibers to be in
a bound state (Ling et al., 1993, p. 201e202). This conclusion is
supported by current estimates, according to which the proportion
of intrinsically disordered proteins in the whole proteome is about
17%, and 30e50% of the remaining proteins contain large unstruc-
tured regions (Finazzi-Agro, 2018). Thus, the total amount of pro-
teins that can effectively adsorb water varies in the range of
50e70% (17 plus 30e50). Some of the outcomes of the develop-
ment of our notions concerning adsorbed water in the living cell
and the physiological implications of its existence are set out in Ling
(2006).
It follows from the data that the properties of the sorption phase
of water are determined by the adsorbent protein, its amino acid
composition, and their sequence. However, a feature common to all
sorption aqueous phases that develop on an adsorbent is a network
of stronger hydrogen bonds, which distinguishes and separates it
from the bulk water. Thus, the data on the similarity of proteinoids
and IDPCs make it possible to suppose that the first abiogenic
peptides were IDPCs, which were capable of adsorbing water and
forming phase-based (i.e. membraneless) compartments which
have the fundamental physical properties needed for the origin of
life.
In conclusion, it is noteworthy that the sorption aqueous phase
should not be seen as a rigid structure that is defined once and for
all. The dynamic nature of hydrated water is that the residence time
of a water molecule within a phase is longer than its residence time
in a volume of unmodified water of the same size (Rani and Biswas,
2015a). This difference (no matter how small) should be of some
physiological significance; e.g. it will lead to the emergence of
concentration gradients of solutes. The diversity of the properties of
proteins will be matched by the diversity of the physical properties
of the sorption phase of water, whereas the effect of ligands (which
interact with the peptide) on these properties will help lay the
groundwork for the formation of relevant signaling pathways,
Please cite this article as: Matveev, V.V., Cell theory, intrinsically disordered proteins, and the physics of the origin of life, Progress in Biophysics
and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.04.001
11
regulatory mechanisms, and adaptation behavior through changes
to the sorption properties of protein phasers. From the standpoint
of this approach, sorption properties of proteins determine all
physical aspects of cellular functions.
5. Intrinsically disordered proteins as the physical basis of the
biophase
Based on the approach adopted herein, cell theory requires that
we look for life's origins in an intermediate cell-like system.
However, the latter's inner structure seems to remain a mystery to
us if we look at its nature from the standpoint of the membrane-
centric model, whose tenets have now been followed for 140
years. Indeed, if we are to be consistent, from the standpoint of the
membrane model, the origin of life would rely on the origin of a
(living) membrane, with all its channels, carriers and pumps
(Matveev, 2017). However, the origin of such a membrane implies
the following: (1) spontaneous formation of heavy proteins with a
complex structure that are capable of performing vital functions;
(2) spontaneous association of these proteins and lipids, which
involves the formation of a fully functional membrane; (3) spon-
taneous formation of systems that generate the energy required for
membrane mechanisms (e.g. pumps) to work.
Curiously, over the past few decades mainstream science has
failed to produce a single piece of evidence that would point toward
the possibility of the living membrane or a component thereof (e.g.,
the Na/K-pump) emerging spontaneously, even under ideal labo-
ratory conditions. There have been attempts to bypass this by
assuming that key components in a full-on biological membrane
(which imparts to the protocell a set of fundamental physical
properties) could not emerge instantly, but in a stage-by-stage
fashion on minerals or in ponds by way of chemical evolution.
However, these ideas seem to lack cogency (Matveev, 2017). There
is another scenario that is becoming increasingly apparent: the first
spontaneously formed peptides were short and had a limited
amino acid composition, but their evolutionary progress could only
have taken place inside the biophase (which they had formed) in
physical conditions that are physically similar to those in the living
cell.
From the standpoint of the phase-centric approach, the conti-
nuity of physical properties between the protocell and the living
cell has to be maintained, as the organization of both systems is
grounded in the same universal phenomenon, i.e. adsorption on the
molecular surface of peptides. With that said, the unity of the
physical properties of the biophase and the living cell, as well as
their invariance, is substantiated by considerable experimental data
(Matveev, 2017), and the principle of invariance is a distinctive
feature of the phase approach to the origin of life.
For the phase protocell to emerge, short peptides are needed,
and the possibility of them emerging spontaneously (up to
14 amino acid residues) in abiotic conditions has been demon-
strated many times (Yu et al., 2017). However, there have also been
claims of the possibility of synthesis of peptides of 56 amino acid
residues on mineral surfaces (Paecht-Horowitz et al., 1970; Paecht-
Horowitz and Eirich, 1988). Data on proteinoids attest to the first
peptides being small, whereas we also know that these short
peptides specifically are poor in secondary structures (Kovacs et al.,
2017). Let us consider the following two factors: (1) the limited
number of amino acids (out of the 10 varieties) available on the
early Earth (Longo et al., 2013), and (2) the simplicity of the for-
mation of short peptides. The formation of a considerable number
of proto-peptides with linear regions is quite apparent. For
instance, the resulting peptides of 20e40 amino acid residues
manifoldly had repeated linear regions (Blaber and Lee, 2012).
Thus, the phase-based approach provides the necessary
12 V.V. Matveev / Progress in Biophysics and Molecular Biology xxx (xxxx) xxx
experimental validation of this possibility of short peptides forming
during the earliest stages of chemical evolution.
Among the first peptides, apart from IDPCs, there must also have
been peptides with a rigid conformation capable of playing only a
supportive (structural) role that would ensure the stable architec-
ture and integrity of the protocell. That said, for the processes
necessary for future cell functions inside the protocell, there is a
need for the ability of primeval peptides to change their sorption
properties in response to changes in physical and chemical condi-
tions of the external and internal environments. Only in that case
can the preconditions for the formation and evolution of special
structures and relevant functions emerge. Similar to photocells
(which transform one type of energy into another), IDPCs trans-
form certain physical interactions into others (Tompa et al., 2015;
Best, 2017). Apparently, the program for these transformations is
laid down in the primary structure of peptides, whereas their
biological purport is to change the sorption properties in such a way
as to ensure a physiologically significant flow of substances from
the environment into the cell and vice versa in response to changes
in the external conditions.
For the protocell to form, phasers (including IDPCs) needed to
unite. We have already ascertained that proteinoids are capable of
forming very firm microspheres, but we also know that even very
short peptides (15 residues) are capable of interacting with each
other, which involves the formation of sustainable aggregates
(Pappu et al., 2008). Thus, the ability of the first peptides, including
IDPCs, to associate with each other, a process that involves the
formation of a membraneless phase protocell, is quite plausible.
From the standpoint of comparative protocell and living cell
physiology (Matveev, 2017), the key properties of IDPCs are: (1)
their conformation mobility, (2) their ability to adsorb water, and
(3) their ability to adsorb Kþ (the cell's main cation) in the presence
of Naþ (however, experimental evidence regarding the ability of
IDPCs to selectively interact with ions is needed). Peptides having
these properties would also be capable of engaging in many other
interactions useful for life.
6. Functioning of the protocell as a cyclic transition between
two states
The ability of IDPCs to respond to weak impacts with confor-
mation changes would enable the protocell to reversibly rebuild its
structure. From a physiological standpoint, the following 2 states of
the protocell of interest are: “there is a phase” and “there is no
phase” (“there is an adsorbed water” and “there is no adsorbed
water”). The absence of transitions between these states will mean
that the protocell is incapable of implementing exchange of sub-
stances in the internal environment and with the outside world.
The “there is a phase” state is the principal state of the protocell (a
resting state), as it is only in this state that the protocell acts as a
compartment. In this state, the protocell does not exchange sub-
stance with the environment, and internally structural changes
discontinue. In this state, living forms are capable of bearing nearly
complete dehydration (as in vegetal spores) or coming back to life
after being frozen in liquid nitrogen. The “there is no phase” state
opens up potential for interactions inside the protocell and the
exchange of substances with the environment, so it becomes an
active, or excited, state (see below). Continuous transitions by
particular structures and the protocell, as a whole, between these
states create flow of substances inside the protocell and with the
environment. The idea of physiological activity being the result of
recurrent reversible transitions between the 2 states (rest-
dactivity) was first proposed by Ling (1969).
In accordance with the accepted approach, a protocell in resting
state is an associate of physiological atoms with the following
Please cite this article as: Matveev, V.V., Cell theory, intrinsically disordered proteins, and the physics of the origin of life, Progress in Biophysics
and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.04.001
structure and composition: (IDPC)1-(H2O)n-(Kþ)m. In the event the
complex disintegrates as a result of some kind of disturbance,
physical or chemical, it will signify the shifting of physiological
atoms (and the protocell as a whole) into an active state, at which a
sharp change in protein sorption properties occurs (the water de-
sorbs, and Kþ is exchanged for Naþ). Secondary structures emerge
in activated proteins, which bring about significant increases in the
number of valences for interaction with other components of the
protocell and the external environment compared with a resting
state, which leads to significant changes in the physical conditions
in the protocell (or parts thereof), the same way as occurs in the
living cell (Matveev, 2010).
The fundamental physical properties of IDPCs that determine
the physical properties of the protocell thus include the ability to
selectively adsorb vital components from the environment (e.g.,
water, Kþ, amino acids, nucleotides, sugars and lipids) and the
ability to substantially change its sorption properties (e.g., desorb
water, exchange Kþ for Naþ, and exchange certain minor molecules
for others) in response to changes in both external and internal
conditions.
The dynamic nature of inter-protein interactions can be well
illustrated through examples of physical and chemical factors
acting on the living cell (e.g. the excitation of muscles) in the event
of a rise in temperature, an increase in hydrostatic pressure, a
change in the concentration of chemical substances, a change in the
pH environment, protein aggregation; the colloidal particles of the
nucleus and cytoplasm increase in size, the viscosity of cytoplasm
increases, and the equilibrium distribution of solutes between the
cell and the environment changes (Matveev, 2005). If the power of
the disturbance/stimulus is not too high, these changes are
reversible and the cell returns to a resting state. Besides muscle
contraction, these changes can also take place many times over in
the spreading of the nerve impulse, which is a vivid example of
functioning as a multifold reversible transition between the 2
states. Structural changes can also occur when protein complexes
with different compositions interact with each other (Matveev,
2000, Fig. 2). Reversible structural changes can also be observed
with microspheres (models of the protocell) (Fox and Yuyama,
1964; Fox, 1965), which is testimony to the primeval nature of
excitation, accompanied by the formation of temporary protein
associates (Matveev, 2010), without which it would be impossible
to imagine structures that perform a certain function emerging in
the protocell.
The structures of the protocell could have experienced cyclic
transitions between the 2 states under the following conditions:
variation in diurnal temperature, geological zones with unstable
temperature conditions, partial drying-out in the intertidal zone,
periodic mechanical impacts in the breaker (surf) zone, and diurnal
or weather-related variations in sunlight. The 2-state theory opens
up an interesting prospect for research into the issue of the origin of
life in the context of the phase-centric approach.
7. Energy for the protocell
The source of energy for the protocell should be internal, not
somewhere outside it. From the standpoint of the phase-based
approach, energy must be generated as a result of reversible
changes in the sorption properties of peptides, while the selection
of primeval peptides imply some way by which those properties
were enhanced. This means that the more effective the adsorption
of water, potassium ions and other small molecules that are needed
for life is, the more sustainable will be phase compartmentaliza-
tion, and the greater the degree to which the physical conditions
inside the protocell will match the needs of life processes depen-
dent on energy.
 V.V. Matveev / Progress in Biophysics and Molecular Biology xxx (xxxx) xxx
If the structure of the first peptides was not an accident (see
above), we should not regard interactions of peptides with other
ions and molecules that strengthen or weaken their sorption
properties as accidental. Interactions of this kind are a way for the
environment to influence the sorption properties of peptides and,
through these the physical properties of protocells, while reversible
changes in these properties are the first physical form of the
response protocells to changes in external factors. We will consider
the issue of how ligands can influence protein using ATP as the
example.
When ATP binds to proteins, it confers on the macromolecule a
considerable negative charge (Riseman and Kirkwood, 1948), due to
which the elements of the polypeptide chain will push away from
each other, existing secondary structures will vanish, bringing the
protein conformation closer to the linear configuration, and inter-
protein interactions will become much weaker due to a decline in
the number of secondary structures needed for this kind of inter-
action. As a result of an enlargement of the adsorption surface for
the water, the hydrophilicity of the protein increases. For instance,
ATP is capable of turning an opaque suspension of colloidal acto-
myosin particles into a clear hydrogel (Spicer, 1951) and a poly-
lysine solution into a 2-phase system, a process that involves the
formation of coacervate droplets (Nakashima et al., 2018), which
are aqueous phases. This phase-forming effect of ATP on proteins is
the result, not of ATP splitting, but the formation of a sustainable
ATP-protein complex. Substances that boost the solubility of hy-
drophobic substances are called hydrotropes, ATP being one of
them (Patel et al., 2017). The role of hydrotropes in the origin of life
is topic for exciting new research.
The energy of adsorption of ATP by myosin is 12e13 kcal/mol
(Wolcott and Boyer, 1974). The adsorption of ATP, which acts as an
integral unsplit anion (Riseman and Kirkwood, 1948; Botts and
Morales, 1951), leads to the release of a considerable amount of
energy. The act of adsorbing any molecule - not to mention ATP
with its considerable charge - will inevitably influence electron
density distributions on the molecular surface of a protein and
consequently will change the force and selectivity of any interac-
tion between its functional groups and other components of the
solution (Da Silva et al., 2014). For this reason, the energy of
adsorption of ATP must not be regarded as the result of only its local
interaction with the binding site on the protein surface. A contri-
bution to this quantity (12e13 kcal/mol) will be made by changes in
all interactions of a protein due to its binding with ATP. Conse-
quently, the calorimeter gives us the total thermal effect of all in-
teractions in the ATP þ protein þ water þ dissolved substances
system. The question arises as to whether the ATP-PA (physiological
atom) complex can serve as the source of energy for biological work
when it is destroyed?
At first glance, the free energy of this complex is at a minimum,
otherwise it would not have formed spontaneously. However, there
are examples where overcoming the energy barrier (which is a
measure of stability in a system) destroys the molecule, with large
amounts of energy being released (e.g., nitroglycerin). Perhaps the
destruction of the (IDPC)1-(H2O)n-(Kþ)m supramolecular complex,
stabilized by secondary (not covalent) bonds can also be accom-
panied by the release of energy. Activation energy (negligible as it is
in the case of non-covalent bonds) can be reduced even more if ATP
is not torn off from protein but catalytically split right at the binding
site. After the splitting of ATP, water and Kþ desorb (as a result of a
weakening of the affinity of the polypeptide backbone of protein to
water and that of carboxyl groups to Kþ) and become free. Besides,
there may be an increase in peptides’ conformation mobility after
the water shell is removed. Thus, we are presented with a picture of
a transition from binding to freeing, from order to disorder. Can this
kind of structural transformation of the physiological atom serve as
Please cite this article as: Matveev, V.V., Cell theory, intrinsically disordered proteins, and the physics of the origin of life, Progress in Biophysics
and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.04.001
13
the sources of energy for the protocell?
Besides the transformation of secondary non-covalent bonds, a
certain amount of energy in a biophase with a resting state is
accumulated in the form of concentration gradients, which emerge
as a result of the following processes: the exclusion of certain ions
(notably Naþ, Hþ, Cl) from the adsorbed water phase and
adsorption of others by the peptide (essentially Kþ). During the
transition of the physiological atom to an active state, its sorption
properties change, water and other adsorbed components are
freed, and concentration gradients are smoothed out.
The idea that the source of free energy for biological work is the
resting state, which is developed with ATP having a key role, was
first proposed by Ling (1984, p. 314e315). On the whole, this idea
can be summarized as follows: a combination of several physical
phenomena may serve as the source of energy for life processes; all
of them, directly or indirectly, are associated with the ability of
proteins to adsorb water and ions. Biological work can be realized in
the form of the interaction of activated proteins with each other
and in the emergence of new gradients (for example, diffusion
ones, arising directly at the moment of destruction of the physio-
logical atom). The enzymatic splitting of ATP results in decompo-
sition of the ATP-PA complex, with the protocell shifting into a
lower free-energy state. This, the source of energy for the protocell,
is not some specific covalent energy-rich bond, but a system of non-
covalent physical interactions, which makes this source distributed,
not tied, to a specific bond. This mechanism of energy provision is a
matter that should be of interest to physicists. However, the ther-
modynamic analysis of this problem meets with considerable dif-
ficulties in the case of small-sized phases (Tovbin, 2017), which are
the physiological atom and protocell.
ATP is curiously a hydrophobic molecule. The logarithm of its
octanol-water distribution coefficient is 1.64 (the coefficient for
chloroform is 1.97) (Leo et al., 1971). It is clear that ATP's hydro-
phobicity is associated with an adenine residue. As an amphiphilic
molecule, ATP can interact with peptides not just electrostatically,
but by way of binding to a macromolecule's hydrophobic parts, in
which, considering the conformation flexibility of IDPCs, temporary
ATP binding sites can form. When there are changes in environ-
mental parameters, the same centers can transform into a catalytic
center that splits ATP. The likelihood of this scenario is substanti-
ated by data that suggest even very short peptides can have cata-
lytic activity (Brack, 2007).
The example with ATP also shows the way other ligands can act
(e.g., Ca2þ), which, along with ATP, can change sorption properties
of peptides, changing their conformation and helping fine-tune the
macromolecule. While it may also be possible to regard other
hydrotropes as ATP's forerunners, the most plausible are related
compounds e inorganic and organic phosphates. The forerunners
must possess one mandatory property, i.e. the ability to influence
the peptide in a way similar to ATP, and comparatively easily in
physiological conditions to clear out the binding sites, which is an
important condition for the release of free energy and transition of
particular peptides, peptide complexes, and protocells, as a whole,
to an active state.
If proto-peptides had been self-determined, their ability to
selectively adsorb vital substances was not accidental too. The
accumulation of solutes in the protocell created the conditions for
the first chemical reactions, which subsequently became in our
terms “biochemical”, while the ability of peptides to change their
sorption properties in the rest-activity-rest cycle did not let the
protocell freeze in one of those states, which would be tantamount
to death (i.e. have none of the attributes that led to the activity we
call “life”. Thus, cyclic changes in the physical properties of the
protocell invested it with dynamism, whose role in the origin of life
we have yet to comprehend.
14 V.V. Matveev / Progress in Biophysics and Molecular Biology xxx (xxxx) xxx
8. Conclusions
Extending cell theory by showing that a cell can originate solely
from a protocell with the same physical properties helps to view
the emergence/evolution of cells from a different angle. Above all,
we may ask ourselves, which physical properties should be seen as
the essence of the dynamism that culminated in a viable and pro-
liferative cell? Thus, any model that possesses the same physical
properties as the living cell will help us understand better the
origin of life.
The primary focus in the context of the issue of the origin of life
suggested herein should be the sorption properties of peptides.
Adsorption acts as a universal physical phenomenon that engen-
ders other physical phenomena potentially vital to the origination
of life. A physical model in which only a single phenomenon is the
cause of many others may potentially simplify the (physical) anal-
ysis of the living cell and its origin, by bringing phenomena that
seem heterogeneous together into a single focus. It may help to
differentiate between 2 major types of phasers, those with a stable
conformation and those with an internal disordered structure. The
former act can as a structural framework for the emergence of the
living cell, whereas the latter could have led to mechanisms that are
required to sustain life processes.
A system's physical state is determined by a particle that is
present in it in the greatest quantity. A particle of this kind in
aqueous phases is water. The formation of aqueous phases based on
biologically significant phasers is the simplest compartmentaliza-
tion mechanism d arguably the principal condition for the origin of
life. Thanks to the forces of adsorption, a biophase is capable of: (1)
separating solutes in space; (2) concentrating solutes; (3) orienting
solutes; (4) speeding up chemical reactions; (5) transforming a
resting state into an active state and vice versa; (6) generating
energy for biological work. Experimentally the possibility of
spontaneous formation of a biophase under conditions that are
similar to those that might have existed on the early Earth has been
proven. Acknowledging the phase as a necessity for compartmen-
talization means the beginning of profound revision of our under-
standing of physical mechanisms underlying the separation of
solutes inside the cell and between the cell and the environment.
Hitherto, at least over most of the last century, the membrane
somehow acquired by early cells has taken center stage in deter-
mining bias in concentration and activities that “separate” cells
from their environment. The membrane can no longer be seriously
viewed as a unique structure without which compartmentalization
would have been impossible, and from which the living cell could have
arisen. This simply begs the even more awkward questions of how
the (cell) membrane arose in the first place, and to what extent it is
the prime regulator of the living state, or more probably a com-
plementary development that allowed cells to assume an even
wider range of abilities under the huge range of environmental
states that would be met and to which adaptation (evolution its
widest sense) is literally vital.
The target of natural selection is in the sorption properties of
(poly)peptides. The critical factor is with a biophase that optimally
combines effective compartmentalization, with the potential for
major transformation in structure and properties. Reversible tran-
sitions from rest to activity impart to the protocell the properties of
a significant physical machine and a chemical reactor that has
achieved a state we refer to as physiological.
It may be worth focusing on the following relevant issues in
further investigation into the origin of life from a perspective of the
sorption approach:
1. What are the causes behind the self-determination of the pri-
mary structure of peptides?
Please cite this article as: Matveev, V.V., Cell theory, intrinsically disordered proteins, and the physics of the origin of life, Progress in Biophysics
and Molecular Biology, https://doi.org/10.1016/j.pbiomolbio.2019.04.001
2. Is it possible for the molecular surface of a phaser to selectively
adsorb certain ions, amino acids, and nucleotides and not bind
others which are not needed for life?
3. What are the characteristics of the equilibrium distribution of
substances between concentrated solutions of IDPCs and the
bathing medium? How is this distribution influenced by the
molecular characteristics of IDPCs, ligands, and physical condi-
tions? The findings from this research would help characterize
more accurately the role of IDPCs with respect to living cells and
the origin of life.
4. Can there emerge in a biophase the conditions for the synthesis
of long peptides (needed for the formation of globular proteins)
and polynucleotides? This stage in the origin of life could be
called intra-biophasic chemical evolution.
5. Can structural transformations of a biophase be a source of
energy for physical processes and chemical reactions that lead
to the emergence of life?
Declaration of interest
The authors declare no conflict of interest.
Acknowledgments
I am very grateful to Richard Wiggins, Andrey Liashenko,
Michael Scherr for their searching, but fruitful, criticism. I also
appreciate Timur Kazbekov and Andrey Guschin's assistance in the
preparation of this document and to Bernard Delalande for the
creative embodiment of the physiological atom in the Graphical
Abstract. My special thanks to Denys Wheatley in discussing many
of its awkward concepts and quibbles, and has helped present this
article in fine idiomatic English. I thank James Clegg for insightful
editorial comments. This research did not receive any specific grant
from funding agencies in the public, commercial, or not-for-profit
sectors.
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