In the Classroom
edited by
Concepts in Biochemistry
Molecular Handshake: Recognition through Weak
Noncovalent Interactions
Parvathi S. Murthy
Department of Chemistry and Biochemistry, Georgian Court University, Lakewood, NJ 08701; murthy@georgian.edu
After nearly a century of anatomical study of geckos and
their ability to adhere to and move rapidly along vertical walls
and ceilings, the mechanism of this dry adhesion has been
recently determined by Autumn et al. (1). The Tokay gecko’s
foot has nearly five thousand keratinous hairs, each of which
contains hundreds of projections terminating in a spatula-
shaped structure. The size and shape of these millions of hy-
drophobic tips or setae lead to remarkably strong adhesion
to any surface (hydrophilic or hydrophobic) by van der Waals
interactions. Collectively, this adhesion is strong enough to
hold the gecko in place on a wall or ceiling. However, the
interaction of each seta with the surface is weak and can be
broken easily and gradually, nearly one interaction at a time,
allowing the animal to move on. This example illustrates the
significance of noncovalent interactions—ability to be formed
and broken easily without much expenditure of energy—af-
fecting the behavior of living and nonliving matter.
The noncovalent interaction between molecules—the
handshake in the form of electrostatic interactions: van der
Waals interactions, hydrogen bonding, or charge transfer in-
teraction—can be found in all matter. Among these, the weak
interactions (some electrostatic interactions, van der Waals
interactions, and hydrogen bonding) are of particular impor-
tance because of the ease with which they can be formed and
broken. These interactions among molecules of a homoge-
neous substance are responsible for determining their bulk
properties: melting point, boiling point, viscosity, surface ten-
sion, and so forth. The interactions between molecules of two
different substances are significant in influencing the rates of
chemical reactions, effectiveness of chromatographic separa-
tions, and molecular recognition in biological processes. The
knowledge of noncovalent interactions between substances is
utilized in the development of new materials and commercial
products with specific utility. This article traces the develop-
ment of our thinking about weak noncovalent interactions,
highlights their salient features, and suggests ways for a com-
prehensive exposition of the principles of these noncovalent
interactions in undergraduate chemistry curricula.
History of Noncovalent Interactions
Our present ideas of interaction between chemical sub-
stances have emerged over centuries. In 1743, Clairault en-
visioned interparticle forces between water and glass and
between particles of water to explain capillary rise of water
in a narrow glass tube (2). The idea that the properties of
matter were related to interaction between atoms or molecules
started emerging in the 19th century with the derivation of
1010 Journal of Chemical Education • Vol. 83 No. 7 July 2006
William M. Scovell
Bowling Green State University
Bowling Green, OH 43403
W
the ideal gas equation of state
P V = N kB T (1)
where P is pressure, V is volume, N is the number of mol-
ecules, kB is Boltzman’s constant, and T is the absolute tem-
perature. This derivation assumed that gas molecules had
negligible volume (point molecules or atoms) with no inter-
action between them. Although this implied that solids, liq-
uids, and nonideal gases could possess interactions between
atoms or molecules, it was late 19th century when the fact
that molecules repel at short ranges and attract at long ranges
was established (2). In 1873, J. D. van der Waals, after study-
ing a number of real gases that exhibited deviation from the
ideal gas equation under certain conditions, successfully
modified the eq 1 to
a
P + 2
V − b = N0 kBT (2)
V
–
where V is molar volume and N0 is Avogadro’s number (3).
The parameter a relates to the strength of intermolecular at-
tractive interactions and b relates to the effective volume of
the spheres (repulsive interactions). Van der Waals considered
atoms or molecules of real gases to be hard spheres that had
certain extensions in space (not mass points) and even as neu-
tral species attracted each other at long range. Equation 2 re-
duces to the ideal gas equation when a and b are zero. There
was no clear understanding about the nature of these univer-
sal molecular attractions, but eq 2 provided for the first time
quantitative information about the interactions.
Early in the 20th century, Reinganum (1903), Debye
(1912), and London (1927) contributed to a better under-
standing of intermolecular forces (2). Reinganum made an
attempt to relate the interactions to the structure of molecules
by proposing the presence of a “bipole” (a pair of opposite
charges separated by a constant distances rigidly located
within a molecule). This was strengthened by early investi-
gations by Debye on permanent dipoles. Soon it became ap-
parent that not all molecules had permanent dipoles.
London’s publication on covalent bonding in H2 molecule
led to an understanding of the chemical bonding within this
molecule and the repulsive forces that operate at short dis-
tances. Following this, London also provided the first theory
of the long-range attractive interactions (known as London
forces) using quantum mechanics. The presence of a weak
bond between certain molecules, involving hydrogen (hydro-
gen bonding), was proposed in 1919 and 1920 (4).
• www.JCE.DivCHED.org
 In the Classroom

Nature of Noncovalent Interactions to be disrupted. This article is limited to the discussion of

In all matter, when atoms, ions, or molecules (of the
same or different substances) approach each other to a prox-
imity of ∼1 nm, there will be negligible overlap of electron
clouds.1 However, there can be noncovalent attractive inter-
actions between them. The various types of noncovalent in-
teractions are: (i) ion–ion, (ii) ion–dipole, (iii) ion–induced
dipole, (iv) dipole–dipole (v) dipole–induced dipole (vi) Lon-
don dispersion forces (induced dipole–induced dipole inter-
actions), (vii) hydrogen bonding interactions, and (viii) charge
transfer complexes. The noncovalent interactions among sub-
stances with no net charge, iv–vi, are often collectively termed
van der Waals forces. The nature and extent of noncovalent
interactions (i–viii) is determined by the type of interacting
species. The interaction energy2 depends on the nature of
species involved, their relative orientation, and their separa-
tion. In the case of solids (macroscopic or microscopic
objects or molecular species), surface uniformity (on a na-
nometer scale) will determine the extent of “contact” and
hence the extent of noncovalent interactions between them
(1, 5). In liquid, solution, or gaseous phase, there is a better
chance of approach to such close distances and hence better
interaction.
The above interactions can also be characterized as weak
or strong noncovalent interactions. Weak interactions are
those that can be disrupted by thermal kinetic energy of the
system3 and are transient (lifetime 10᎑12 s) in nature (6). The
strength of these interactions under the existing conditions,
taken collectively over the bulk of the substance, influences
the behavior of this form of matter. Strong interactions (ion–
ion and charge transfer types4) require changes in conditions
such as chemical reagents, pH, temperature, or ionic strength
weak noncovalent interactions: van der Waals interactions and
hydrogen bonding. The nature of weak noncovalent interac-
tions is described in Table 1.
When chemical species approach each other closely, there
will be London forces of attraction between them. In addi-
tion, there may also be other types of weak interactions de-
pending on the nature of the interacting species. Although,
individually weak and operating over brief periods of time,
collectively this form of molecular recognition mechanism
can significantly influence the properties of chemical and bio-
logical systems. Through differential interaction with the re-
actants, products, and the transition state, solvents influence
the rate of chemical reactions. Solvent interactions can also
alter the mechanism and hence the products of the reaction.
In chromatography, the stationary phase and the mobile phase
compete to interact with the analytes effecting their separa-
tion. While the nonspecific but collective effect was signifi-
cant in the last two examples, specific noncovalent
interactions are responsible for enzyme catalysis, allosteric
regulation of gene expression, and signal transduction pro-
cesses in biological systems. The ease of formation and cleav-
age of intermolecular forces between a protein (enzyme) and
its substrate (catalysis), a protein and its effector ligand (al-
losteric regulators), or a receptor protein and its specific sig-
nal molecule (signal transduction pathway) leads to
establishment of a dynamic equilibrium between the “free”
and the “bound” states of the protein. The existence of this
equilibrium is crucial to the biological function of the pro-
tein. The availability of the binding substance (substrates, ef-
fectors, or signal molecules) shifts the equilibrium between
the free (inactive) and bound (active) states of the protein
and thus determines the its biological activity under the ex-

Table 1. Nature of Weak Noncovalent Interactions

Types of Interacting Nature of Interaction:
Noncovalent Interaction
Substances, A and B (a) Type of Force (b) Interaction Energya
A: Ionic (a) Electrostatic
ion–dipole
B: Polar covalent (b) 0.2–4.0 kJ/mol (at separation distance of ~1 nm).
Electrostatic
A: Ionic or polar covalent Strength falls of with r ᎑2 for ion–dipole and r ᎑4
ion–induced dipole for ion–induced dipole interactions.
B: Nonpolar covalent
dipole–dipole A, B: Polar covalent (a) Electrostatic
(b) 0.5–4 kJ/mol (at separation distance of ~1 nm).
van der Waals dipole–induced dipole
A: Polar Strength falls of with r ᎑3 for dipole–dipole and r ᎑6
(substances with B: Nonpolar covalent for dipole–induced dipole interactions.
no net charge) induced dipole–induced (a) Attractive interactions between fluctuating charges.
dipole (London forces, All substances (b) 0.2–2 kJ/mol (at separation distance of ~1 nm).
Dispersion forces)b Strength falls of with r ᎑6.
Hydrogen Bonding
Requires interaction between specific atoms, A: Compounds with strongly
as shown (A is the donor, B is the acceptor) polar covalent bonds containing
(a) Donor–acceptor/electrostatic interaction
A–H + :B → A–H:B hydrogen atom as part
(b) 10–40 kJ/mol (at separation distance
Weakens A–H bond. Distance between of the dipole
between A and B < 0.4 nm) (~2 kJ/mol for those
H and B in the complex can be lower B: Compounds with lone pair
involving pi electron acceptors).
than sum of their van der Waals radii. electrons or negative charges
Directional (usually 180⬚). or pi electrons
Stoichiometric.
a
The magnitude depends on the net charge, size of the species, separation distance (r), and temperature. Its value is inversely proportional to rn (n
varying from 2–6 for various interactions). The values indicated here are typical values used in common text books. bMajor contributor to noncovalent
interactions except in small, highly polar molecules. Often referred to as hydrophobic interactions, in biological systems.

www.JCE.DivCHED.org • Vol. 83 No. 7 July 2006 • Journal of Chemical Education 1011

 In the Classroom
isting condition. The weak intramolecular interactions within
the protein, nucleic acid, and carbohydrate chains support
retention of the gross three-dimensional structures of the
biopolymers while allowing for regional conformational flex-
ibility necessary for the biological function. A biological cell
membrane is a phenomenal structure that is held together
only by noncovalent forces. This structure gives the mem-
brane fluidity and determines its functions, such as self-as-
sembly, self-healing, and the ability to separate contents while
allowing specific substances to cross it.
Noncovalent Interactions in the Undergraduate
Chemistry Curriculum
One of the main goals of chemical education is to teach
students to understand the relationship between molecular
structure or composition of matter and its properties. The
relationship between structure and property (established by
studying known matter or processes) is the tool that can lead
to the design of new materials and processes. Much of the
matter we come across in everyday life is not an individual
atom or molecular species but is heterogeneous in nature. To
gain an insight into the structure–property relationships re-
quires a good understanding of the structure or composition
of matter (chemical bonding) and the nature of noncovalent
interactions between molecular species as they exist in close
proximity to one another. Such an important universal con-
cept deserves greater emphasis in chemistry curriculum. The
following paragraphs describe the extent of coverage of non-
covalent interactions in the current undergraduate chemis-
try curriculum.
A significant portion of the general chemistry curricu-
lum is allocated to teaching covalent or ionic bonding inter-
actions that make up individual molecules and network
structures. Although matter is usually not found as single
atomic or molecular species, the textual resources allocated
to the topic of interactions between molecules or their influ-
ence on properties of matter is limited to pure substances.
Some general chemistry textbooks show the following cover-
age of noncovalent interactions (7): The kinetic theory of gases
(in the chapter on gases) includes a statement such as attrac-
tive and repulsive interactions between gas molecules are neg-
ligible in the gaseous state. There is little, if any, description
of what these forces are. The chapter also includes a section
on van der Waals’s equation and PV兾RT versus P behavior of
real and ideal gases. Usually, following this chapter is the chap-
ter on intermolecular forces in pure solids and pure liquids
with definitions of various noncovalent interactions and their
influence on physical properties: surface tension, viscosity, and
boiling point. The chapter on properties of solutions describes
the influence of the nature of solutes and solvents on dissolu-
tion with a few typical examples. The chapter includes the
effect of solutes on colligative properties of solvents in a quan-
titative manner without delving into the nature of solute–sol-
vent interactions that lead to the colligative properties. The
chapters on intermolecular forces and properties of solutions
also, generally, fall into chapters 10–14 of the textbook—to-
wards the end of the semester—and may not get full cover-
age. The chapter on reaction kinetics rarely mentions the
importance of the role of solvents in influencing the kinetics
or mechanisms of chemical reactions. The laboratory experi-
1012 Journal of Chemical Education • Vol. 83 No. 7 July 2006
mental content may include an experiment on the influence
of the nature of solutes and solvents on dissolution (8).
Typical organic chemistry textbooks often introduce the
topic on noncovalent interactions in early chapters and briefly
describe their influence on solubilities of compounds with
specific functional groups in water (9). The laboratory syn-
thesis experiments do not incorporate the importance of the
choice of solvents in these reactions. The importance of non-
covalent interactions in determining the effectiveness of chro-
matographic separations is briefly included, if at all, even
though this technique could make up a significant portion
of the laboratory experiments. The chapters on carbohydrates,
proteins, nucleic acids, and lipids refer to noncovalent inter-
actions as they describe the structure of these compounds.
The fact that the biological activity of these molecules, very
often, is entirely a consequence of their three-dimensional
structure, is not emphasized. Physical chemistry and analyti-
cal chemistry courses may include spectroscopic methods to
study hydrogen-bonding interaction but is limited to few spe-
cific systems, for example, keto–enol tautomerization of
acetylacetone (10). Biochemistry texts describe these inter-
actions as contributing to structural aspects of biomolecules
and do not describe the importance of the weak interactions
in binding processes—ease of formation and breakage (11).
There have been nearly fifty publications in this Journal
in the past ten years on topics such as molecular recognition
or intermolecular forces. Most of these articles describe ex-
periments pertaining to one specific system, involving hy-
drogen-bonding interactions, or are mostly directed to
upper-level (physical chemistry or biochemistry) laboratory
instruction. Several recent articles in this Journal have iden-
tified the need for better instruction in this field; Rebek et
al. have also identified the lack of sufficient time for teach-
ing noncovalent interactions in undergraduate chemistry cur-
ricula (12). Henderleiter et al. have discussed how students
in organic chemistry classes, while able to give definition and
even identify hydrogen bonding in substances, had difficulty
relating the influence of this interaction on the properties of
substances (13). They point the cause to the confusion in
the descriptions found in general chemistry and organic
chemistry textbooks. While discussing the teaching of
noncovalent interactions in a biochemistry course, Cox has
identified the shortcomings of biochemistry textbooks in de-
scribing the various noncovalent interactions (14).
In conclusion, the concepts of noncovalent interactions
are included in a sporadic way in various chemistry classes
but the bigger picture of the nature of molecular recognition
through weak noncovalent interactions, universality (when
any substance comes in contact with any other substance)
and the significance of their weakness or transient nature, is
not portrayed in the curriculum. Considering all matter is
“chemical”, chemistry students should be able to identify the
type of interactions between any two “objects” (macroscopic,
microscopic, or molecular). They should be able to suspect
noncovalent interactions when they see a paint sticking to
one surface and not to another. To provide this broader per-
spective, in addition to emphasizing the content that is al-
ready in current textbooks, it is important to reinforce the
concept of noncovalent interactions throughout the under-
graduate curriculum.5 The main concepts, such as the na-
ture of chemical reactions, dynamic equilibrium, methods of
• www.JCE.DivCHED.org

separation, and bulk properties, are an integral part of every
chemistry course. Utilizing a lecture to bring together the con-
cepts of noncovalent interactions encountered throughout the
semester, in different contexts, would be time well spent.
Examples such as the gecko’s walk illustrate these principles
well. Laboratory instruction on experiments in which the stu-
dents are using mixtures is a good opportunity to provoke
thinking about the interactions (which substance is recog-
nizing which other substance and to what degree) and any
possible effects of these interactions. All chemistry students
must be aware of the value of chemical principles in expand-
ing knowledge in other disciplines. The influence of nonco-
valent interactions on biological processes and materials
research and development are good examples of such appli-
cations. A description of some examples is available in the
Supplemental Material .W
Summary
Molecular recognition through noncovalent interactions,
as an interdisciplinary science, is contributing enormously to
chemical genomics, drug discovery, and materials design (16,
17). New methods of detection and quantification of these
interactions are developed at an increasing pace (18). Many
students will go on to industrial or academic research labo-
ratories to pursue knowledge in this area. Noncovalent in-
teractions and the consequent molecular recognition should
be an important component of undergraduate chemistry cur-
riculum.
Acknowledgment
The author is grateful to Jannette L. Carey, Department
of Chemistry, Princeton University, Princeton, NJ, for help-
ful discussions.
WSupplemental Material
Examples of the influence of weak noncovalent interac-
tions on chemical and biological systems with references to
literature are available in this issue of JCE Online.
Notes
1. The van der Waals radii of nonmetallic atoms range from
0.12 nm for hydrogen to 0.22 nm for iodine.
2. Spectroscopic methods (IR and NMR), diffraction (X-ray
and neutron diffraction), thermochemical (calorimetry of heats of
mixing or dilution, determination of bulk properties, enthalpies or
determination of equilibrium constants for the formation of non-
bonded complexes), and computational methods are used for quali-
tative and quantitative study of these interactions.
3. For gaseous molecules, at 300 K, the thermal energy is of
the order of ∼3.7 kJ兾mol (5).
4. Interaction energy of ion–ion interactions is of the order
of ∼300 kJ兾mol and charge transfer interactions is of the order of
∼50 kJ兾mol.
5. Recent textbooks have adopted a different approach to in-
troducing noncovalent interactions: introducing the concept in ear-
lier chapters, including examples from biological chemistry along
with those of small molecules or dedicating a chapter to molecular
recognition (15).
www.JCE.DivCHED.org • Vol. 83 No. 7 July 2006
In the Classroom
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