Mr. Rakesh Bhagwat Jagtap

M. Pharmacy {Sem -Second}

Dept. of Pharmaceutical Chemistry

R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur

PARAMETERS

Introduction to Molecular Modeling

Types of Molecular Modeling Methods

-Quantum Mechanics

-Molecular Mechanics

Discreteness between both QM & MM

Applications

References

What is Molecular Modeling ???

Quantum Mechanics

Molecular Mechanics

“Nuclei of Molecule is Stationary

with respect to the electrons”

Electronic Schrödinger Equation

ĤelΨel = EelΨel

Types of

QM

ab

initio

Methods

Semi-empirical Methods

Hartree-Fock Approximation

Advantages-

Does not depend on experimental data

Small systems

System requiring high accuracy

Disadvantages-

Computationally expensive and time

consuming

Density functional theory (DFT) is based not on the

wave function, but rather on

the electron probability density function or electron

density function, commonly called

simply the electron density or charge density.

Density functional theory has its conceptual roots in the Thomas-Fermi model .• They used a statistical model to approximate the distribution

of electrons in an atom.

Kohn-Sham Equations and Density Functional Models

The density functional theory of Hohenberg, Kohn and Sham is based

on the fact that the sum of the exchange and correlation energies of a

uniform electron gas can be calculated exactly knowing only its

density.

• The electron density is the square of wave function and integrated over electron coordinates.

Kohn-Sham Equations and Density Functional Models

In the Kohn-Sham formalism, the ground-state electronic

energy, (E) is written as a sum of the kinetic energy,

(ET) the electron nuclear interaction energy, (EV) the

Coulomb energy,(EJ) and the exchange energy,(Exc).

E = ET + EV + EJ + EXC

Except for ET, all components depend on the Total Electron Density.

Advantages-

Does not depend on experimental data

Small systems

System requiring high accuracy

Disadvantages-

There are difficulties in using density functional theory to

properly describe intermolecular interactions, especially van der

Waals forces (dispersion); charge transfer excitations; transition

states, global potential energy surfaces and some other strongly

correlated systems

Semi-empirical quantum chemistry method is based

on the Hartree–Fock formalism, but make many

approximations and obtain some parameters from

empirical (Experimental) data.

They are very important in computational chemistryfor treating large molecules where the full Hartree–Fock method without the approximations is tooexpensive. The use of empirical parameters appears to allowsome inclusion of electron correlation effects into themethods.

Advantages-

Semi-empirical calculations are very fast compared to ab initioand even to DFT

Medium-sized systems (hundreds of atoms)

Disadvantages-

Does depend on experimental data

Small systems Low accuracy- for ex.

There are a number of situations when quantum mechanics is superior to molecular mechanics:

Modeling Systems With Metal Atoms

Increased Accuracy

Computing Reaction Paths

Modeling Charge Transfer

Predicting Spectra

Modeling Covalently Bound Inhibitors

Computing Enthalpies Of Covalent Bond Formation Or Breaking

Quantum Mechanics

Molecular Mechanics

Molecular Mechanics

The molecular mechanics energy equation is a sum of terms that

calculate the energy due to bond stretching, angle bending,

torsional angles, hydrogen bonds, van der Waals forces, and

Coulombic attraction and repulsion.

Molecular mechanics methods are the basis for other methods,

such as construction of homology models, molecular dynamics,

crystallographic structure refinement, and docking .

The basic functional form of an inter-atomic potential encapsulates both

bonded terms relating to atoms that are linked by covalent bonds, and

non-bonded. The specific decomposition of the terms depends on the

force field, but a general form for the total energy in an additive force field

can be written as

Etotal = Ebonded + Enonbonded

where the components of the covalent and non-covalent contributions are

given by the following summations:

Ebonded = Ebond + Eangle + Edihedral

Enon-bonded = Eelectrostatic + Evan der Waals

AMBER (Assisted Model Building and Energy Refinement)

CHARMM (Chemistry at Harvard Molecular Mechanics)

GROMOS (Groningen Molecular Simulation package)

OPLS (Optimized Potential for Liquid Simulations)

CFF (Consistent Force Field)

COMPASS (Condensed-phase Optimized Molecular Potentials for Atomistic Simulation Studies)

MMFF (Merck Molecular Force Field)

Etc......

Parameters

Quantum MechanicsMolecular

Mechanicsab initio

Method

Semi-Empirical

Method

Molecular Size Small Medium Large

Principle

Calculations

Electronic

Energy

Electronic

Energy

Nuclear

Energy

Time Required Days Hours Minutes/Hours

Accuracy High Low Low

Data Required Computational Experimental Computational

Cost Affairs High Medium Low

Discreteness Between Both QM & MM

Novel TechniqueQM/MM-

This is the ‘Hybrid’ of quantum and molecular mechanics

The QM/MM procedure is applicable when the system can be

partitioned into two regions;

one region (the ‘active site’) requires an accurate QM calculation of

its potential and

the second region (the rest of the system) acts as a perturbation on

the active site and can be treated with an approximate and fast MM

calculation of its potential.

By using a quantum mechanical calculation, we can treat bond-

breaking and bond-forming accurately at the active site yet still take

into account the role of the surrounding atoms using MM.

Applications

To Calculate The Geometries and Energies

Computing Enthalpies of Bond Formation or Breaking

In Structure Based Drug Designing (Docking Studies)

To Monitor Reaction Path

Applications

To Calculate The Geometries and Energies

Applications

Computing Enthalpies of Bond Formation or Breaking

In Structure Based Drug Designing (Docking Studies)

To Monitor Reaction Path

Applications

To Calculate Frequencies

⇦ IR Spectra by Experiment

⇦ IR Spectra by MM

Applications

Applications

Leach A. R.; 2001; Molecular Modeling Principles and Applications; 2nd ed;

Pearson Hall; England; pp 1-247.

Young D. C.; 2009; Computational Drug Design: A Guide for Computational and

Medicinal Chemists; John Wiley & Sons, Inc.; New Jersey; pp 119-123, 187-194.

Hinchliffe A.; 2008; Molecular Modelling for Beginners; 2nd ed; John Wiley &

Sons, Inc.; New Jersey; pp 49-94.

Herhe W. J.; 2003; A Guide to Molecular Mechanics and Quantum Chemical

Calculations; Wavefunction, Inc.; USA; pp 1-60.

Atkins P., Freidman R.; 2005; Molecular Quantum Mechanics; 4th ed; Oxford

University Press Inc.; New York; pp 249, 250, 288-338.

Lewars E.; 2003; Computational Chemistry: Introduction to the Theory and

Applications of Molecular and Quantum Mechanics; Kluwer Academic

Publishers; London; pp 1-378.

Raha K., Peter M., Ning Yu B., Wollcott A., Westerhoff L., Merz Jr K.; 2007; The

Role Of Quantum Mechanics In Structure-based Drug Design; Drug Discovery

Today; Volume 12; no. 17/18; pp 725-731.

Vanommeslaeghe K., Hatcher E., Acharya C., Kundu S., Zhong S., Shim J.,

Darian E., Guvench O., Lopes P., Vorobyov I., Mackerell Jr A.; 2010; CHARMM

General Force Field: A Force Field for Drug-Like Molecules Compatible with the

CHARMM All-Atom Additive Biological Force Fields; Journal of Computational

Chemistry; Volume 31; pp 671–690.