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COMPUTATIONAL CHEMISTRY

Computational chemistry uses result of theoretical chemistry

incorporated into efficient computer programmed to
calculate structure and properties of molecule.

It calculate the properties of molecule such as structure,

relative energy, charge distribution, dipole moment,
vibrational frequency, reactivity and other spectroscopic
quantity.

Computational chemistry range from highly accurate (Ab

initio method to less accurate (semiemiprical) to very
approximate (molecular mechanics).
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 Advantage of Computational
Chemistry
1) It allows the medicinal chemist for use the computational
power of computer for measurement of
 Mol. geometry
 electron density
 electrostatic potentional
 conformational analysis
 different types of energies.

2) Determination of structure of ligand and target through X-

ray crystallography and NMR spectroscopy.

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3) Docking of ligand in rececpter active sites and exact
measerment of geometric and energetic favor ability of
such interaction.

4) Comparssion of various ligands throgth various

parameters.

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 What does Computational
Chemistry Calculate?
 Energy, Structure and Properties

• What is the energy for a given geometry?

• How does energy vary when geometry changes?
• Which geometries are stable?
• How do atoms rearranges to form new molecules?
• How do stucture, energy, and properties change over time?

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 What does Computational
Chemistry Calculate?
 Examples
• Ionization energy (HOMO energy).
• Electron affinity (LUMO energy).
• Proton affinity.
• Electronic excitation energy (UV-Vis spectra).
• NMR chemical shifts and coupling constants.
• Reaction path and barrier height.
• Reaction rate.

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Molecular modeling method
The three dimensional shape of both ligand and target site
may be determined by X-ray crystallography or
computational method.

The most common computational methods are based on

either molecular or quantum mechanics.

Both this approaches produce equation for total energy of

the structure.

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 Computational method

 There are two main types method depending on the

starting point theory.

• Classical method :-
Are those method use Newton mechanics to model
molecular system.

• Quantum chemistry method:-

Which makes use of Quantum mechanics to model the
molecular system. This method used different type of
approximation to solve Schrödinger’s Equation.
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 Classical Methods
1. Molecular Mechanics
2. Molecular Dynamics.

 Quantum Mechanics Methods

1. Semi empirical Methods.
2. Ab initio Methods.
3. Density functional Theory.

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 Computational Chemistry

Quantum Mechanics (QM) Molecular Mechanics (MM)

Hybrid QM / MM Semi-empirical (SE)

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 Molecular Mechanics

• Molecular mechanics programs use equations based

on classical physics to calculate force fields.

• Atoms treated as spheres, bonds as springs and electron

are ignored.

• It assume that the total potential energy (Etotal) of

molecule is given by sum of all the energies of attractive
and repulsive forces between atom in structure.

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 The molecular mechanics equation

E = EB+EA+ED+ENB

EB = The energy involved in the

deformation bond either by
stretching or compression.

EA = The energy involved in the angle

bending .

ED = The torsional angle energy.

ENB = The energy involved in the interaction

between atoms that are not directly 03/31/24

12
bonded.
 Force Field
Force field refers to calculation of the interaction and
energies between different atoms between bond
stretching, angle bending, torsional angle and non-
bonded interaction.
Force field ignores the electronic distribution while
Quantum mechanics considers electronic distribution
of molecule.

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Classical empirical force field

1) AMBER(Assisted Model Building and energy

Refinement)
2) CHRAM (Chemistry at Harvard Macromoleculer
Mechanics)
3) CVFF(Consistent Valence Force Field)

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 Molecular Model Using Molecular

Mechanics

 The molecular models are created by either using an existing

commercial force field computer program or assembling a
model from structural fragments held in the database of
molecular modeling program.

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 Molecular Dynamics
• Molecular dynamics is a molecular mechanics program designed to
mimic the movement of atoms within a molecule.

• Molecular dynamics can be carried out o a molecule to generate

different conformation which on energy minimization, give a range
of stable conformation. Alternatively bonds can be rotated in a
stepwise process to generate different conformation.

• Molecular dynamics can also be used to find minimum energy

structures and conformational analysis.

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Fig-: Plot of change in the energy with the rotation about C 2-C3 bond In butane
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 Quantum mechanics
• Quantum mechanics is based on arrangement of electrons
of molecule and interaction of those electron with
electron and nuclei of other molecule.

• It based on the realization that electron and all material

exhibit wavelike properties.

• The Quantum mechanics based on finding solution to

Schrödinger wave equation.

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 Schrödinger’s Equation
 The Schrödinger equation is the basis of quantum mechanics and gives a
complete description of the electronic structure of a molecule. If the
equation could be fully solved all information of a molecule could be
determined.

Hψ = Eψ
Where
H=Hamiltonian operator
Ψ =wave fuction
E =Energy system
To solve schrodinger equation was found to difficult. Hydrogen-total
energy of hydrogen (E) can be described as the sum of kinetic energy and
potential energy of its two component i.e. proton and electron.

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Schrödinger equation for this relationship can written,

Hψ=(k+v)=Eψ

Where as
K = kinetic energy
V = potential energy

 Describes both the wave and particle behavior of electrons.

 The wave function is described by ψ while the particle behavior

is represented by E.
 In systems with more than one electron, the wave function is
dependent on the position of the atoms; this makes it important to
have an accurate geometric description of a system.

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 Quantum Mechanics Method

1. Ab inito method
2. Semiemperical method
3. Density functional theory

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 Ab Initio method

• Ab initio translated from Latin means from “first

principles”.

• This refers to the fact that no experimental data is used

and computations are based on quantum mechanics.

• It derived directly from theoretical principle.

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Different Levels of Ab Initio Calculations

1. Hartree-Fock (HF)

2. Density Functional Theory (DFT)

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 Hartree-Fock (HF)

• The simplest ab initio calculation.

• It based on Central field approximation.

• The major disadvantage of HF calculations is that

electron correlation is not taken into consideration.

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 Density Functional Theory

• Considered an ab initio method, but different from other

ab initio methods because the wave function is not used
to describe a molecule.

• Density functional theory in which total energy is

expressed in term of total electron density is used.

• DFT methods take less computational time than HF

calculations and are considered more accurate.

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 Semi Empirical Method

• Semi-empirical quantum methods, represents a middle road

between the mostly qualitative results available from
molecular mechanics and the high computationally
demanding quantitative results from ab initio methods.
• Semi empirical methods use experimental data to
parameterize equations.
• Like the ab initio methods, a Hamiltonian and wave
function are used.
• Less accurate than ab initio methods but also much faster.
• Capable of calculating transition states and excited states.

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 Choice of Method

The method of calculation based on what calculation needs

to done and size of molecule.

Molecular mechanics useful for

 Energy minimization
 Identifying stable conformation
 Energy calculation for specific conformations
 Studying molecular motion
 Studying different conformation.

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 Quantum mechanics method are suitable for
calculating,

 Molecular orbital energies

 Heat formation for specific conformation
 Dipole moment
 Bond dissociation energy
 Transition-state geometries and energies

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Computational Cost vs. Accuracy
Accuracy

Quantum Mechanical
Methods

Molecular Mechanics
Number
10 100 1000 10,000 of Atoms
Atom and Small
Molecules Large Compounds
and Nano-clusters Proteins,
DNA, RNA …
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 Quantum Mechanics vs. Molecular

Mechanics

Quantum Mechanics Molecular Mechanics

1. Correctly describes the 1. Does not properly describe

Bond- breaking the Bond-breaking and
and Bond-forming Bond-forming
2. Application limited to 2. Can treat more than 10,000
Hundreds of Atoms Atoms

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 Quantum mechanics Molecular mechanics

1) More expensive 1) Less expensive

1) More time 2) Less time

1) More computing power 3) Less computing power

4) Used for small molecule 4) Used for large molecule

5) It can calculate electronic 5) It cannot calculate electronic

properties like electron density properties like electron density

6) Application limited to hundreds 6) Applicable to more than ten

of atom thousands of atoms
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 Energy minimization

• Energy minimization produces the nearest stable

conformation to the structure presented and not
necessarily the global conformation.

• Energy minimization involved alteration of bond length,

bond angle, torsion angle and non-bonded interaction .

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 Energy minimization

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 Moleculer mechanics energy
minimization
• Molecular mechanics is an approach of energy minimization
that find stable, low energy conformation by changing the
geometry of a structure.

Type of algorithms
1)Steepest Descent procedure

2)Conjugate gradient procedure

3)Newton –Raphson procedure

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 Selection of energy minimization
algorithms
• The selection of energy minimization algorithms depends
on size of system and current state of optimization.

• When molecule having larger than 200 atoms then

conjugate gradient procedure.

• When molecule having less than 200 atoms then newton-

raphson procedure.

• When molecule having larger than 10Kcal/mol/A then

Steepest Descent.

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 Computer graphics

In Moleculer modeling, data produced are converted as

visual image on a computer
Images displayed as,
 Space fill model
 Ball and stick model
 CPK model
 Mesh model
 Ribbon model

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Stick model Ball and stick model CPK model

Ribbon representation of
Mesh representation
38 of Aspirin 03/31/24
dihydrofolate reductase
Chapter 9: Computation Concepts
Computational Chem3D supports a number of powerful
computational chemistry methods and extensive
Chemistry Overview visualization options.

Computational chemistry extends beyond the Computational Methods

traditional boundaries separating chemistry from
physics, biology, and computer science. It allows Overview
the exploration of molecules by using a computer
Computational chemistry encompasses a variety
when an actual laboratory investigation may be
of mathematical methods which fall into two
inappropriate, impractical, or impossible. As an
broad categories:
adjunct to experimental chemistry, its
significance continues to be enhanced by •Molecular mechanics—applies the laws of
increases in computer speed and power. classical physics to molecular nuclei without
explicit consideration of electrons.
Aspects of computational chemistry include:
•Quantum mechanics—relies on the Schrödinger
•Molecular modeling.
equation to describe a molecule with explicit
•Computational methods. treatment of electronic structure.
•Computer-Aided Molecular Design (CAMD). Quantum mechanical methods can be subdivided
•Chemical databases. into two classes: ab initio and semiempirical.

•Organic synthesis design. The generally accepted method classes are shown
in the following chart.
While a number of different definitions have been
proposed, the definition offered by Lipkowitz
and Boyd of computational chemistry as “those
aspects of chemical research that are expedited
Computational Chemistry Methods
or rendered practical by computers” is perhaps
the most inclusive.
Molecular modeling, while often taken to include
computational methods, can be thought of as the
Molecular Quantum Mechanical Methods
rendering of a 2D or 3D model of a molecule’s
Mechanical Methods
structure and properties. Computational
methods, on the other hand, calculate the
structure and property data necessary to render
the model. Within a modeling program, such as Semiempirical Ab Initio
Chem3D, computational methods are referred to Methods Methods
as computation engines, while geometry engines
and graphics engines render the model.

Chem3D Chapter 9: Computation Concepts • 123

Chem3D provides the following Choosing the Best Method
methods:
• Molecular mechanical MM2 method.
Not all types of calculations are possible for all
• Semiempirical Extended Hückel, MINDO/3, methods and no one method is best for all
MNDO, MNDO-d, AM1 and PM3 methods purposes. For any given application, each
through Chem3D and CS MOPAC. method poses advantages and disadvantages.
• Ab initio methods through Chem3D’s The choice of method depend on a number of
Gaussian interface. factors, including:
• The nature of the molecule
• The type of information sought
Uses of Computational
• The availability of applicable
Methods experimentally determined parameters (as
Computational methods calculate the potential required by some methods)
energy surfaces (PES) of molecules. The potential • Computer resources
energy surface is the embodiment of the forces of
interaction among atoms in a molecule. From
The three most important of the these criteria
the PES, structural and chemical information
are:
• Model size—The size of a model can be a
about a molecule can be derived. The methods
differ in the way the surface is calculated and in limiting factor for a particular method. The
the molecular properties derived from the limiting number of atoms in a molecule
energy surface. increases by approximately one order of
The methods perform the following basic types of magnitude between method classes from ab
calculations: initio to molecular mechanics. Ab initio is
• Single point energy calculation—The energy limited to tens of atoms, semiempirical to
of a given spacial arrangement of the atoms hundreds, and molecular mechanics to
in a model or the value of the PES for a thousands.
given set of atomic coordinates. • Parameter Availability—Some methods
• Geometry optimization—A systematic depend on experimentally determined
modification of the atomic coordinates of a parameters to perform computations. If the
model resulting in a geometry where the net model contains atoms for which the
forces on the structure sum to zero. A parameters of a particular method have not
3-dimensional arrangement of atoms in the been derived, that method may produce
model representing a local energy minimum invalid predictions. Molecular mechanics,
(a for example, relies on parameters to define a
stable molecular geometry to be found without force-field. Any particular force-field is only
crossing a conformational energy barrier). applicable to the limited class of molecules
• Property calculation—Predicts certain for which it is parametrized.
physical and chemical properties, such as • Computer resources—Requirements increase
charge, dipole moment, and heat of in relative to the size of the model for each of
formation. methods can perform more
Computational the methods.
specialized functions, such as conformational
searches and molecular dynamics
simulations.

124 • Chapter 9: Computation Concepts Chem3D

 Ab initio: The time required for performing Quantum Mechanical Methods
computations increases on the order of N 4, Applications Summary
where N is the number of atoms in the model.
Useful information determined by
Semiempirical: The time required for
quantum mechanical methods includes:
computation increases as N3 or N2, where N is
the number of atoms in the model. • Molecular orbital energies and
coefficients.
MM2: The time required for performing
• Heat of Formation for evaluating
computations increases as N2, where N is the
number of atoms. conformational energies.

In general, molecular mechanical methods • Partial atomic charges calculated from

are computationally less expensive than the molecular orbital coefficients.
quantum mechanical methods. The • Electrostatic potential.
suitability of each general method for
particular applications can be summarized • Dipole moment.
as follows. • Transition-state geometries and energies.
Molecular Mechanics Methods
• Bond dissociation energies.
Applications Summary
The semiempirical methods available in
Molecular mechanics in Chem3D apply Chem3D and CS MOPAC apply to:
to:
• Systems containing thousands of • Systems containing up to 120 heavy atoms
atoms. and 300 total atoms (in CS MOPAC for
• Organic, oligonucleotides, peptides, Windows) or 60 heavy atoms and 120 total
and saccharides. atoms (in CS MOPAC for Macintosh).

• Gas phase only (for MM2). • Organic, organometallics, and small

Useful techniques available using MM2 oligomers (peptide, nucleotide, saccharide).
methods include: • Gas phase or implicit solvent environment.
• Energy Minimization for locating stable • Ground, transition, and excited states.
conformations.
Ab initio methods, available through the
• Single point energy calculations for
Gaussian interface, apply to:
comparing conformations of the same
molecule. • Systems containing up to 30 atoms.
• Searching conformational space by varying a • Organic, organometallics, and molecular
single dihedral angle. fragments (catalytic components of an
enzyme).
• Studying molecular motion using Molecular
Dynamics. • Gas or implicit solvent environment.
• Study ground, transition, and excited
states (certain methods).

Chem3D Chapter 9: Computation Concepts • 125

The following table summarizes the method Potential Energy Surfaces
types
Method Type Advantages Disadvantages Best For A potential energy surface (PES) can describe:
•A molecule or ensemble of molecules having
Molecular Least intensive Particular force Large
Mechanics computationally— field applicable systems constant atom composition (ethane, for example)
(MM2) fast and useful with only for a limited (thousands of or a system where a chemical reaction occurs.
limited computer class of molecules atoms)
Uses classical resources •Relative energies for conformers (eclipsed and
physics Does not calculate Systems or
Can be used for electronic processes staggered forms of ethane).
Relies on force- molecules as large properties with no
field with breaking or
as enzymes Requires
embedded forming of
experimental data bonds
empirical
(or data from ab Different potential energy surfaces are generated
parameters
initio) for for:
parameters
•Molecules having different atomic composition
(ethane and chloroethane).
Semiempirical Less demanding Requires Medium- •Molecules in excited states instead of for the
computationally experimental data sized systems
(MOPAC)
than ab initio (or data from ab (hundreds of same molecules in their ground states.
methods initio) for atoms)
Uses quantum
parameters •Molecules with identical atomic composition but
physics
with different bonding patterns, such as
Capable of Systems propylene and cyclopropane.
Uses calculating Less rigorous than involving
experimentally transition states electronic
ab initio methods
derived empirical and excited states transitions Potential Energy Surfaces (PES)
parameters
The true representation of a model’s potential
energy surface is a multi-dimensional surface
Uses whose dimensionality increases with the number
approximation of independent variables. Since each atom has
extensively
three independent variables (x, y, z coordinates),
visualizing a surface for a many-atom model is
Ab Initio Useful for a broad Computationally Small
systems (tens impossible. However, we can generalize this
(Gaussian) range of systems intensive
of atoms) problem by examining any 2 independent
variables, such as the x and y coordinates of an
Uses quantum Does not depend
physics on Systems atom, as shown below.
experimental data involving
Mathematically electronic
rigorous—no Capable of transitions
empirical calculating
parameters transition states Molecules or
and excited states systems
without
available
experimental
data (“new”
chemistry)

Systems
requiring
rigorous
accuracy

126 • Chapter 9: Computation Concepts Chem3D

 All the minima on a potential energy surface of a
molecule represent stable stationery points where
the forces on atoms sum to zero. The global
minimum represents the most stable
conformation; the local minima, less stable
conformations; and the saddle points represent
transition conformations between minima.

Saddle Point
Single Point Energy
Potential Energy
Calculations
Local Minimum
Global Minimum Single point energy calculations can be used to
calculate properties of the current geometry of
a model. The values of these properties
depend on where the model currently lies on
The main areas of interest on a potential energy the potential surface as follows:
surface are the extrema as indicated by the
arrows, are as follows: • A single point energy calculation at a global
minimum provides information about the
• Global minimum—The most stable model in its most stable conformation.
conformation appears at the extremum
• A single point calculation at a local minimum
where the energy is lowest. A molecule has
only one global minimum. provides information about the model in one
of many stable conformations.
• Local minima—Additional low energy
• A single point calculation at a saddle point
extrema. Minima are regions of the PES
where a change in geometry in any direction provides information about the transition
yields a higher energy geometry. state of the model.

• Saddle point—The point between two low • A single point energy calculation at any other
energy extrema. The saddle point is defined point on the potential energy surface
as a point on the potential energy surface at provides information about that particular
which there is an increase in energy in all geometry, not a stable conformation or
directions except one, and for which the transition state.
Single point energy calculations can be
slope (first derivative) of the surface is zero.
performed before or after performing an
optimization.
NOTE: At the energy minimum, the energy is not NOTE: Do not compare values from different
zero; the first derivative (gradient) of the energy methods. Different methods rely on different
with respect to geometry is zero. assumptions about a given molecule.

Chem3D Chapter 9: Computation Concepts • 127

Geometry Optimization The following illustration shows some concepts
of minimization. For simplicity, this plot shows
Geometry optimization is used to locate a stable a single independent variable plotted in two
conformation of a model. This should be dimensions.
performed before performing additional
computations or analyses of a model.
Locating global and local energy minima is often
accomplished through energy minimization.
Locating a saddle point is optimizing to a
transition state.
The ability of a geometry optimization to
converge to a minimum depends on the starting
geometry, the potential energy function used,
and the settings for a minimum acceptable
gradient between steps (convergence criteria).

Geometry optimizations are iterative and begin

at some starting geometry as follows:

1. The single point energy calculation is

The starting geometry of the model determines
which minimum is reached. For example, starting
performed on the starting geometry.
at (b), minimization results in geometry (a),
which is the global minimum. Starting at (d)
2. The coordinates for some subset of atoms leads to geometry (f), which is a local
are changed and another single point minimum.The proximity to a minimum, but not
energy calculation is performed to a particular minimum, can be controlled by
determine the energy of that new specifying a minimum gradient that should be
reached.
conformation.
3. The first or second derivative of the energy Geometry (f), rather than geometry (e), can be
(depending on the method) with respect to reached by decreasing the value of the gradient
where the calculation ends.
the atomic coordinates determines how large
and in what direction the next increment of Often, if a convergence criterion (energy
geometry change should be. gradient) is too lax, a first-derivative
minimization can result in a geometry that is
4. The change is made. near a saddle point. This occurs because the
value of the energy gradient near a saddle point,
5. Following the incremental change, the energy as near a minimum, is very small. For example,
and energy derivatives are again at point (c), the derivative of the energy is 0, and
determined and the process continues until as far as the minimizer is concerned, point (c) is
a minimum. First derivative minimizers cannot,
convergence is achieved, at which point the
as a rule, surmount saddle points to reach
minimization process terminates.
another minimum.
NOTE: If the saddle point is the extremum of
interest, it is best to use a procedure that
specifically locates a transition state, such as the
CS MOPAC Pro Optimize To Transition State
command.

128 • Chapter 9: Computation Concepts Chem3D