Molecular Modelling

Syllabus
Potential energy surface: Energy minimisation, geometry optimisation, conformational analysis, global
and local minimum determination, approaches and problems, bioactive vs global minima
conformations, automated methods of conformation search, advantages and limitations of available
softwares.

Molecular modelling or more generally computational chemistry is the scientific field of simulation of
molecular systems.

Molecular modelling allow scientists to use computers to visualize molecules means representing
molecular structures numerically and simulating their behavior with the equations of quantum and
classical physics.

Computational chemistry (also called molecular modelling; the two terms mean about the same thing)
is a set of techniques for investigating chemical problems on a computer.

Computational chemistry is valuable in studying the properties of materials, i.e. in materials science.
Semiconductors, superconductors, plastics, ceramics – all these have been investigated with the aid of
computational chemistry. Such studies tend to involve a knowledge of solid-state physics and to be
somewhat specialized. Computational chemistry is fairly cheap, it is fast compared to experiment, and
it is environmentally safe (although the profusion of computers in the last decade has raised concern
about the consumption of energy and the disposal of obsolescent machines). It does not replace
experiment, which remains the final arbiter of truth about Nature. Furthermore, to make something –
new drugs, new materials –one has to go into the lab. However, computation has become so reliable in
some respects that, more and more, scientists in general are employing it before embarking on an
experimental project, and the day may come when to obtain a grant for some kinds of experimental
work you will have to show to what extent you have computationally explored the feasibility of the
proposal.

Questions commonly investigated computationally are:

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1. Molecular geometry: the shapes of molecules – bond lengths, angles and dihedrals.
2. Energies of molecules and transition states: this tells us which isomer is favored at equilibrium, and
(from transition state and reactant energies) how fast a reaction should go.
3. Chemical reactivity: for example, knowing where the electrons are concentrated (nucleophilic sites)
and where they want to go (electrophilic sites) enables us to predict where various kinds of reagents
will attack a molecule.
4. IR, UV and NMR spectra: these can be calculated, and if the molecule is unknown, someone trying
to make it knows what to look for.
5. The interaction of a substrate with an enzyme: seeing how a molecule fits into the active site of an
enzyme is one approach to designing better drugs.
6. The physical properties of substances: these depend on the properties of individual molecules and on
how the molecules interact in the bulk material. For example, the strength and melting point of a
polymer (e.g. a plastic) depend on how well the molecules fit together and on how strong the forces
between them are.

Tools of Computational Chemistry

In studying these questions computational chemists have a selection of methods at their disposal. The
main tools available belong to five broad classes:

Molecular mechanics is based on a model of a molecule as a collection of balls (atoms) held together
by springs (bonds). If we know the normal spring lengths and the angles between them, and how much
energy it takes to stretch and bend the springs, we can calculate the energy of a given collection of balls

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and springs, i.e. of a given molecule; changing the geometry until the lowest energy is found enables us
to do a geometry optimization, i.e. to calculate a geometry for the molecule. Molecular mechanics is
fast: a fairly large molecule like a steroid (e.g. cholesterol, C27H46O) can be optimized in seconds on a
good personal computer.

Ab Initio calculations (ab initio, Latin: “from the start”, i.e. from first principles”) are based on the
Schrodinger equation. This is one of the fundamental equations of modern physics and describes,
among other things, how the electrons in a molecule behave. The ab initio method solves the
Schrodinger equation for a molecule and gives us an energy and wavefunction. The wavefunction is a
mathematical function that can be used to calculate the electron distribution (and, in theory at least,
anything else about the molecule). From the electron distribution we can tell things like how polar the
molecule is, and which parts of it are likely to be attacked by nucleophiles or by electrophiles.

The Schrodinger equation cannot be solved exactly for any molecule with more than one electron.
Thus approximations are used; the less serious these are, the “higher” the level of the ab initio
calculation is said to be. Regardless of its level, an ab initio calculation is based only on basic physical
theory (quantum mechanics) and is in this sense “from first principles”. Ab initio calculations are
relatively slow: the geometry and IR spectra of propane can be calculated at a reasonably high level in
minutes on a personal computer, but a fairly large molecule, like a steroid, could take perhaps days. The
latest personal computers, with 2 or more GB of RAM and a thousand or more gigabytes of disk space,
are serious computational tools and now compete with UNIX workstations even for the demanding
tasks associated with high-level ab initio calculations.

Semiempirical calculations are, like ab initio, based on the Schrodinger equation. However, more
approximations are made in solving it, and the very complicated integrals that must be calculated in the
ab initio method are not actually evaluated in semiempirical calculations: instead, the program draws
on a kind of library of integrals that was compiled by finding the best fit of some calculated entity like
geometry or energy (heat of formation) to the experimental values. This plugging of experimental
values into a mathematical procedure to get the best calculated values is called parameterization (or
parametrization). It is the mixing of theory and experiment that makes the method “semiempirical”: it
is based on the Schrodinger equation, but parameterized with experimental values (empirical means
experimental). Of course one hopes that semiempirical calculations will give good answers for
molecules for which the program has not been parameterized.
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 Semiempirical calculations are slower than molecular mechanics but much faster than ab initio
calculations. Semiempirical calculations take roughly 100 times as long as molecular mechanics
calculations, and ab initio calculations take roughly 100–1,000 times as long as semiempirical. A
semiempirical geometry optimization on a steroid might take seconds on a PC.

Density functional calculations (DFT calculations, density functional theory) are, like ab initio and
semiempirical calculations, based on the Schrodinger equation However, unlike the other two methods,
DFT does not calculate a conventional wavefunction, but rather derives the electron distribution
(electron density function) directly. A functional is a mathematical entity related to a function. Density
functional calculations are usually faster than ab initio, but slower than semiempirical.

Molecular dynamics calculations apply the laws of motion to molecules. Thus one can simulate the
motion of an enzyme as it changes shape on binding to a substrate, or the motion of a swarm of water
molecules around a molecule of solute; quantum mechanical molecular dynamics also allows actual
chemical reactions to be simulated.

Potential Energy Surface (PES)

A potential energy surface (PES) is a mathematical function that gives the energy of a molecule as a
function of its geometry. The potential energy surface is typically defined within the Born-
Oppenheimer approximation: electrons are much lighter than nuclei, thus they move much faster and
adjust adiabatically to any change in nuclear configuration. This means that a separate PES is defined
for each possible electronic state. Generally, the dynamics are studied on the ground electronic state
surface.

The Born-Oppenheimer approximation says that in a molecule the nuclei are essentially stationary
compared to the electrons. This is one of the cornerstones of computational chemistry because it makes
the concept of molecular shape (geometry) meaningful, makes possible the concept of a PES.

The Born-Oppenheimer Approximation is the assumption that the electronic motion and the nuclear
motion in molecules can be separated. Born-Oppenheimer (named for its original inventors, Max Born
and Robert Oppenheimer) is based on the fact that nuclei are several thousand times heavier than

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electrons. The proton, itself, is approximately 2000 times more massive than an electron. In a
dynamical sense, the electrons can be regarded as particles that follow the nuclear motion adiabatically,
meaning that they are ``dragged'' along with the nuclei without requiring a finite relaxation time. This,
of course, is an approximation, since there could be non-adiabatic effects that do not allow the electrons
to follow in this ``instantaneous'' manner, however, in many systems, the adiabatic separation between
electrons and nuclei is an excellent approximation.

Consider a diatomic molecule AB. In some ways a molecule behaves like balls (atoms) held together
by springs (chemical bonds); in fact, this simple picture is the basis of the important method molecular
mechanics. If we take a macroscopic balls-and-spring model of our diatomic molecule in its normal
geometry (the equilibrium geometry), grasp the “atoms” and distort the model by stretching or
compressing the “bonds”, we increase the potential energy of the molecular model (see following
Figure). The stretched or compressed spring possesses energy,
by definition, since we moved a force through a distance to distort it. Since the model is motionless
while we hold it at the new geometry, this energy is not kinetic and so is by default potential
(“depending on position”). The graph of potential energy against bond length is an example of a
potential energy surface. A line is a one-dimensional “surface”; we will soon see an example of a more
familiar two-dimensional surface rather than the line of Figure 1.

Figure 1
Real molecules behave similarly to, but differ from our macroscopic model in two relevant ways:

1. They vibrate incessantly (as we would expect from Heisenberg’s uncertainty principle: a stationary

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molecule would have an exactly defined momentum and position) about the equilibrium bond length,
so that they always possess kinetic energy (T) and/or potential energy (V): as the bond length passes
through the equilibrium length, V = 0, while at the limit of the vibrational amplitude, T = 0; at all other
positions both T and V are nonzero. The fact that a molecule is never actually stationary with zero
kinetic energy is usually shown on potential energy/bond length diagrams by drawing a series of lines
above the bottom of the curve (Fig. 2) to indicate the possible amounts of vibrational energy the
molecule can have (the vibrational levels it can occupy). A molecule never sits at the bottom of the
curve, but rather occupies one of the vibrational levels, and in a collection of molecules the levels are
populated according to their spacing and the temperature. We will usually ignore the vibrational levels
and consider molecules to rest on the actual potential energy curves or (see below) surfaces.

2. Near the equilibrium bond length qe the potential energy/bond length curve for a macroscopic balls-
and-spring model or a real molecule.

Figure 2

Energy minimization
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In computational chemistry energy minimization (also called energy optimization or geometry
optimization) methods are used to compute the equilibrium configuration of molecules and solids.
Energy minimizatiom methods can precisely locate minimum energy confirmation by mathematically
“homing in” on the energy function minima (one at a time).  The goal of energy minimization is to
find a route (consisting of variation of the intramolecular degrees of freedom) from an initial
confirmation to nearest minimum energy confirmation using the smallest number of calculations
possible.

Energy is a function of the degrees of freedom in a molecule: bonds, angles, dihedrals.

Knowing the stable conformers of a molecule is important because it allows us to understand properties

and behavior based upon structural considerations. Energy minimization is usually carried out to

determine a stable conformer; this same process also is commonly referred to as geometry

optimization.

Energy minimization is a numerical procedure for finding a minimum on the potential energy surface

starting from a higher energy initial structure, labeled "1" as illustrated in Figure 3. During energy

minimization, the geometry is changed in a stepwise fashion so that the energy of the molecule is

reduced, from steps 2 to 3 to 4 as shown in Figure 3. After a number of steps, a local or global

minimum on the potential energy surface is reached.

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Most energy minimization methods proceed by determining the energy and the slope of the function at
point 1. If the slope is positive, it is an indication that the coordinate is too large (as for point 1). If the
slope is negative, then the coordinate is too small. The numerical minimization technique then adjusts
the coordinate; if the slope is positive, the value of the coordinate is reduced as shown by point 2. The
energy and the slope are again calculated for point 2. If the slope is zero, a minimum has been reached.
If the slope is still positive, then the coordinate is reduced further, as shown for point 3, until a
minimum is obtained.

The lowest energy conformation is the set of bond lengths and angles that gives the smallest steric
energy. In other words, bonds find a compromise among competing forces to determine the lowest
energy conformation.

Local minima – relative, Confined in a smaller place, i.e. with limited amount of atoms

Global minima – absolute, Includes the entire energy balance of a molecule

Local minima

1. This is a relative minimum

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 2. Confimed in a smaller place, i.e. with limited amount of atoms

3. Has same neighbourhood which can be (not be) a part of global energy calculations

Global minima

1. This is the absolute minima

2. Includes the entire energy balance of a molecule

3. It is a overall value of a set or function of a energy calculation

Molecules have – Number of degree of freedom – And multiple global minimas – Hence difficult for
larger molecules. So, we can take multiple local minimas and join the results to get a global minima.

The maximum or minimum over the entire function is called an "Absolute" or "Global" maximum or
minimum. There is only one global maximum (and one global minimum) but there can be more than
one local maximum or minimum.

Consider a diatomic molecule AB. In some ways a molecule behaves like balls (atoms) held together
by springs (chemical bonds). If we take a macroscopic balls-and-spring model of our diatomic
molecule in its normal geometry (the equilibrium geometry), grasp the “atoms” and distort the model
by stretching or compressing the “bonds”, we increase the potential energy of the molecular model. The
stretched or compressed spring possesses energy, by definition, since we moved a force through a
distance to distort it – work was done on the spring. Since the model is motionless while we hold it at

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the new geometry, this energy is not kinetic and so is by default potential (“depending on position”).
The graph of potential energy against bond length is an example of a potential energy surface.

Figure: The potential energy surface for a diatomic molecule. The potential energy increases if the
bond length q is stretched or compressed away from its equilibrium value qe. The potential energy at qe
(zero distortion of the bond length) has been chosen here as the zero of energy.

The curves that we see in this figure connect equipotential points on the potential energy surface.
Cutting across one of these curves means going "uphill" or "downhill" in energy.

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The characterization (the “location” or “locating”) of a stationary point on a PES, that is, demonstrating
that the point in question exists and calculating its geometry and energy, is a geometry optimization.
The stationary point of interest might be a minimum, a transition state, or, occasionally, a higher-order
saddle point. Locating a minimum is often called an energy minimization or simply a minimization,
and locating a transition state is often referred to specifically as a transition state optimization.
Geometry optimizations are done by starting with an input structure that is believed to resemble (the
closer the better) the desired stationary point and submitting this plausible structure to a computer
algorithm that systematically changes the geometry until it has found a stationary point.

Conformational analysis

The structure that you built and minimized represents one possible conformer of a molecule. Some

molecules, such as ethane, methanol, or phenol have only one unique conformer. In such situations, the

observed chemical properties of the molecule can be obtained by considering the structure of this one
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conformer. The thermodynamic properties could be obtained by considering structure fluctuations (e.g.

bond vibrations) near the minimum energy geometry. The spectral properties of the molecule can be

obtained by analyzing how the nuclear or electronic structure changes near this energy minimum in

response to external electromagnetic fields. The biological properties can be predicted by considering

how the minimum energy structure interacts with biological macromolecules. Thus, in all such cases

the observed properties of the molecule can be rationalized by studying the minimum energy structure.

Most molecules exist as a mixture of several conformers. For example, cyclohexane has different

energy minima (for chair, boat, twist-boat). The chair conformation is the most stable conformation of

cyclohexane. A second, much less stable conformer is the boat conformation. A third conformation is

produced by twisting the boat (reducing the steric strain) to give the twist or skew-boat conformation.

Consequently the twist boat is slightly more stable than the boat.

In such situations, the observed properties of a molecule cannot be obtained by considering only one of
the conformers. In order to find all the other conformers of the molecule, one can try to draw the
molecule in different shapes, and minimize each shape. However, this is tedious and error-prone
process because for larger molecules we cannot easily guess the shape of all the possible
conformations. Conformational analysis automates this task by finding other molecular structures that
are energy minima on the potential energy surface and ranks them according to their energies. The
structures that have the lowest energy are most abundant.

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It uses computers to generate information such as properties of molecules or simulated experimental

results. Some common computer software used for computational chemistry includes:

1. Gaussian

2. ADF

3. GAMESS

4. MOPAC

5. Spartan

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