MPHY2002: Introduction to Biophysics

Chapter 1: Introduction

One of the remarkable things about the world is how different it looks
at the macroscopic and microscopic scales. With the naked eye, we see
ourselves as individuals that are capable of moving in a single
direction with a single purpose. With the microscope, we see a
tremendous variety of cells in various states of division and death,
each interacting with their local environment in different ways.
Looking further still, we see molecules in continual motion, moving
and colliding randomly, receiving energy and delivering energy to
their surroundings.

Nature has presented us with a challenge: can we appreciate how

events in one size scale are connected to events in another? One way to
move forward is to embrace complexity and to try to find as many
details as possible about all of the molecules in our body. Along these
lines, each detail is a small piece of a large puzzle; they key to solving
the puzzle is to consider how each piece links to its neighbour.

In biophysics, we tend to take a different approach: we try to find

general principles that allow us to explain many different
observations.

In all branches of science, the engine of understanding is a model. A

model is a simplified picture of reality that allows us to explain certain
types of events. One essential aspect of a model is that it generates
predictions that allow us to test its validity. In biophysics, models
provide a bridge between biology and physics. On the biology side,
there is an interesting set of observations that relate to a specific
biological context. On the physics side, the objective is to find a model
that explains those biological observations and provides us with
predictions. The learning process that follows involves pushing the

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boundaries of the model, to try to find new biological observations that

are not accurately predicted, and then to try to figure out how to revise
our model (or whether to toss it out altogether!).

Observations  Model Creation  Predictions

In the following chapters, we will explore several different models

related to cellular-level processes in the human body. One theme that
connects these models is the use of probabilities to account for
processes that are far too complex to be analysed as deterministic
systems. We will focus primarily on processes in the human body that
are related to signalling and movement, with an eye towards clinical
applications. Why? First, biophysics is a huge field with fuzzy
boundaries and we have to start somewhere! Second, this subject is one
of the most dynamic in science today – particularly from the
standpoint of clinical applications – and comprises many elegant
mathematical models.

1.2 Membranes

One feature that all cells have in common is a membrane with which to
separate their internal workings from the external environment). This
cell membrane consists of a double layer of molecules called
phospholipids, which is frequently referred to as a lipid bilayer. The
thickness of the lipid bilayer is 7.5 nm, which is small even at cellular
scales: by comparison, a red blood cell has a diameter of
approximately 7000 nm, which makes its wall thickness only 1/1000
of its diameter!

Each phospholipid molecule has a hydrophobic (water fearing) end and

a hydrophilic (water loving) end; in a bilayer, the phospholipid
molecules are arranged with the hydrophobic ends facing each other.
This arrangement is a very natural one, in the sense that spherical
bilayers will form spontaneously by self-assembly when phospholipids
are placed in an aqueous solution.

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MPHY2002: Introduction to Biophysics

Cross section view of the structures that can be formed by

phospholipids in aqueous solutions. Source: Reference 2.

Lipid bilayers are also found extensively within the cell: they form
internal compartments called organelles that include the nucleus and
mitochondria.

How can biophysical models provide insights about lipid bilayers?

Let’s imagine a conversation between a biologist B and a physicist P.

B: I’ve been up all night and finally finished measuring the

shapes of various lipid bilayer structures in cells. Interestingly,
vesicles are approximately spherical and ….

P: OK, I have a model to explain all your measurements! In

terms of measuring shapes, lipid bilayer structures can be
considered as homogenous. If we integrate the amount of
energy that it takes to deform each little piece of the lipid
bilayer structure, we arrive at a single number – the total
energy. Of all structures with a given surface area, spheres
have the lowest energy. That’s why your vesicles are spherical.

B: That’s interesting, but…

P: Wait, I’m not done: my model predicts that the amount of

energy required to create a spherical lipid bilayer structure is
independent of the radius.

B: But…

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P: That’s it! You took all night to acquire measurements and I

obtained my model in a few minutes!

B: Actually, many structures are not spherical.

P: What? Are you sure?

B: Yes, I have images to prove it.

P: Darn! There’s nothing like an ugly fact to ruin a great theory!

B: Can you explain the new observations?

P: Well, I guess we could add some complexity to our model.

We could hypothesise that there are structures within the cell
that exert tension on cell membranes…

B: I’ll start looking for them!

If only the scientific process went so quickly! It’s worth noting that the
first model that the physicist came up with is not wrong; actually,
according to the principle of Occam’s Razor, it might be the best model
for some contexts because it can explain observations with a small
number of concepts. However, it is incomplete and a recognition of
that fact can lead to progress with our understanding.

1.3 Membrane Proteins

A biological membrane is studded with many types of proteins that

allow for a wide range of interactions between one side of the
membrane and another. For instance, certain proteins form structures
called “ion channels” that are integrated within the membrane and
allow for ions to pass from one side to another.

Ion Channels in a lipid bilayer. Source: Reference 3

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The manner in which a protein interacts with its environment is

determined in large part by its three-dimensional (3D) shape, which is
often referred to as its conformational state. Proteins can assume
different conformational states depending on the contexts in which
they reside. A protein that is a component of an ion channel may
initially assume a conformational state that allows for the flow of ions
through that channel (so that the ion channel is closed). If the protein
undergoes a binding event, it may undergo a conformational state
change that prevents the flow of ions (so that the ion channel is
closed). In this context, the protein is called a receptor and the
molecule that binds to the receptor is called a ligand.

Various receptor types in a lipid bilayer. Source: Reference 4

In a similar manner, a receptor protein that spans the membrane can

act as a sensor: if the portion of this protein that resides in the
extracellular environment binds to a ligand, the protein undergoes a
conformational state change that affects its interactions with
molecules inside its intracellular environment. Ligands can include
hormones, drugs, toxins, and molecules called neurotransmitters that
mediate the flow of information between neurons.

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1.4 Protein Synthesis

Proteins are found not only in biological membranes but throughout

the cell. They are of critical importance in determining the identity of a
cell as well as its function, and they are involved in virtually all cellular
processes. There are over 100,000 types of proteins in our bodies.
Remarkably, biological proteins are constructed from sequences of
only 20 molecules called amino acids. As a result, they are called
polymers because they comprise a large number of similar molecules
called monomers that are bonded together. It’s useful to introduce a
little more terminology: a peptide refers a short polymer of amino
acids; a polypeptide refers to a sequence of peptides, and a protein
refers to a long polypeptide.1

The proteins created by our body are encoded with DNA

(deoxyribonucleic acid) molecules. DNA consists of molecular building
blocks called nucleotides or bases (Adenosine, Thymine, Guanine, and
Cytosine) that are arranged in a sequence of base pairs (A-T and C-G).
Individual amino acids are encoded as sequences of three nucleotides
called codons.

To extract information from DNA for protein production,

complementary copies of a DNA nucleotide sequence are made with
different molecules called messenger RNA (ribonucleic acid), in a
process called transcription. The term “complementary” is used
because the manner in which amino acids are encoded is similar with
DNA and RNA, but with the latter molecule, the nucleotide uracil is
used in place of thymine. Messenger RNA molecules travel out of the
nucleus via structures called nuclear pores, which are composed of
membrane-bound proteins. Outside of the nucleus, an amino acid
sequence is created when individual amino acids are bonded according
to the base pair sequence in messenger RNA, in a process called
translation. Amino acids are matched to corresponding regions on
messenger RNA using small molecules called transfer RNA, with
bonding facilitated by a large complex molecule called a ribosome.2

DNA is a remarkably long molecule, but it in the nucleus it is tightly

folded: it is wound up around proteins called histones. Amazingly, DNA
is still accessible to the cell despite all of this folding. Cells manage to
access its information in DNA by unwinding local regions with
enzymes called helicases. Typically, healthy cells continuously
generate proteins, with the transcription process taking place at many
locations on the DNA molecule simultaneously.

1 There are no specific rules that indicate how many amino acids are in peptides, polypeptides, and
proteins.
2 After synthesis, some polypeptides undergo changes that are known as post-translational modifications,

which include the addition of sugar molecules to form glycoproteins, or associations with non-peptide
molecules such as metal ions (such as the haem in haemoglobin).

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Transcription and translation. Source: Reference 1

Peptide synthesis. Source: Reference 5

A polypeptide created during translation becomes a functional protein

when it folds into its three-dimensional shape. Certain sequences of
amino acids are hydrophobic and others are hydrophilic; an important
determinant of the three-dimensional shape of a protein is how these
sequences interact with each other and their environment. For
instance, in the cytoplasm, proteins may fold in such a manner as to
reduce the hydrophobic regions are close together, with an outer shell
of hydrophilic regions. Membrane proteins tend to fold such that
hydrophobic regions are within the phospholipid bilayer.

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MPHY2002: Introduction to Biophysics

Protein folding showing different motifs, represented as

regions with open and filled circles. Source: Reference 1

Certain repeating sequences of amino acids within a polypeptide tend

to form three-dimensional motifs such as helices that are recognised in
many different proteins. These motifs form what is known as the
secondary structure of a protein. With this terminology, the primary
structure of a protein is simply its sequence of amino acids and the
tertiary structure, is the full three-dimensional shape of the protein.
Some polypeptide chains associate to form proteins with two or more
subunits. This is called the quaternary structure of the protein.

Different graphical representations of a folded protein.

Source: Reference 6

A computational biophysics problem of great interest is to predict the

shape of a protein based on its amino acid sequence. It has proven to
be a very challenging because the number of ways that a protein can
be folded is incredibly large. The stakes involved with solving this so-
called “protein folding problem” accurately are very high. We can
imagine that an accurate solution would present us with a better
appreciation of how sequences of DNA are related to specific cellular

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processes, and additionally we can imagine designing proteins that

could interact with specific molecules in the human body and then
manipulating the DNA of certain microorganisms to produce these
proteins for us.

1.5 Cytoskeleton

Cells have structural elements that are collectively referred to as the

cytoskeleton, which allow them to deform and move. Cytoskeletal
elements include actin filaments and intermediate filaments which
function like cables under tension and thereby maintain cell shape.
They also include microtubules, which act like support beams and
resist compression.3

Rat embryo fibroblast cell imaged using fluorescence

microscopy, showing actin stress filaments (red) and vinculin, a
component of the attachment points for actin (green/yellow).
Source: Reference 7.

Actin filaments, intermediate filaments, and microtubules are all

polymers that can form by self-assembly. In many cells, the process of
polymerisation (creation of polymers) and depolymerisation
(destruction of polymers) takes place continually at different parts of
the cell simultaneously. This provides cells with the ability to
continually change their shapes and mechanical properties to adapt to
their environment. As such, a cell can use its outer membrane to engulf
material (a process called endocytosis) or to expunge material (a
process called exocytosis). Some cells can even crawl and extend parts
of themselves in specific directions.

3Physicist Roger Penrose at Oxford University has postulated that microtubules may play a crucial role in
consciousness. See “the Emperor’s New Mind” for more detail about these ideas.

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Endocytosis. Source: Reference 8

There is another mechanism that implicates cytoskeletal elements in

movement: they act as molecular ladders that can be climbed by
specific molecules. This mechanism allows for muscle cells to contract.
It also allows for miniature molecular motors to transport material
from one part of the cell to another in vesicles. For instance, the
molecular motors dynein and kinesin move along microtubules.
Dynein usually travels towards the cell centre, whereas kinesin usually
travels in the opposite direction. It is fascinating to consider how this
directionality is achieved (how do they “know” which way they are
going)!

Kinesin on a microtubule. Source: Reference 1.

1.6 Energy

Molecules in a cell are in continual motion. Some types of motion are

due to thermal energy and involve elastic collisions; these take place
whether or not the cell is alive. Many other types of motion, such as the
deformation of a cell membrane or the transport of a vesicle, are

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critical for life to persist, and require mechanisms with which cell can
actively expend energy.

There are several mechanisms for energy storage, but by far the most
common involves the molecule ATP (adenosine triphosphate). Energy
from ATP can be released in a process called ATP hydrolysis, in which
the release of a phosphate group is associated with the release of
energy to form ADP (adenosine diphosphate):

ATP  ADP + Energy

ATP is produced with glucose in the presence or absence of oxygen, in

processes known as anaerobic respiration and aerobic respiration,
respectively. For every 1 molecule of glucose, 2-3 molecules of ATP are
produced with anaerobic respiration, whereas 36-38 are produced
aerobic metabolism.4 Aerobic respiration takes place in specialised
elongated cellular organelles called mitochondria; anaerobic
respiration takes place in the space within cells that is outside of
organelles, known as the cytoplasm.

References and Further Reading

1. Nelson, S. Biological Physics: Energy, Information, Life

2. http://en.wikipedia.org/wiki/File:Phospholipids_aqueous_sol
ution_structures.svg
3. Ion channels in lipid bilayer (Digital artwork/Computer
graphic). Credit: Maurizio De Angelis, Wellcome Images
4. Various receptor types on a cell membrane. Medical Art
Service, Munich, Wellcome Images
5. http://upload.wikimedia.org/wikipedia/commons/0/0f/Pepti
de_syn.png
6. http://upload.wikimedia.org/wikipedia/commons/6/6e/Prot
einviews-1tim.png
7. Stress fibres, focal adhesions & lamellae. Catherine Nobes &
Alan Hall, Wellcome Images
8. Endocytosis. Medical Art Service, Munich / Wellcome Images

4 Anaerobic has the advantage of being extremely rapid, so it is useful for activities such as sprinting.

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