molecular mechanics and quantum mechnics

1. Mr. Rakesh Bhagwat Jagtap
M. Pharmacy {Sem -Second}
Dept. of Pharmaceutical Chemistry
R. C. Patel Institute of Pharmaceutical Education and Research,
Shirpur

2. PARAMETERS
Introduction to Molecular Modeling
Types of Molecular Modeling Methods
-Quantum Mechanics
-Molecular Mechanics
Discreteness between both QM & MM
Applications
References

3. What is Molecular Modeling ???

4. Quantum
Mechanics
Molecular
Mechanics

6. “Nuclei of Molecule is Stationary
with respect to the electrons”
Electronic Schrödinger
Equation
ĤelΨel = EelΨel

7. Types
of
QM
ab
initio
Methods
Semi-
empirical
Methods

9. Hartree-Fock Approximation

10. Advantages-
Does not depend on experimental data
Small systems
 System requiring high accuracy
Disadvantages-
Computationally expensive and time
consuming

11. 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.

12. 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.

13. 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.

14. 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

15.  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 chemistry
for treating large molecules where the full Hartree–
Fock method without the approximations is too
expensive.
 The use of empirical parameters appears to allow
some inclusion of electron correlation effects into the
methods.

16. Advantages-
 Semi-empirical calculations are very fast compared to ab initio
and even to DFT
 Medium-sized systems (hundreds of atoms)
Disadvantages-
 Does depend on experimental data
 Small systems
 Low accuracy- for ex.

17. 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

19. Quantum
Mechanics
Molecular
Mechanics

22. 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 .

23. 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

24. 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......

25. Parameters
Quantum Mechanics
Molecular
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

26. Novel Technique
QM/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.

27. 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

28. Applications
 To Calculate The Geometries and Energies

29. Applications
 Computing Enthalpies of Bond Formation or Breaking
 In Structure Based Drug Designing (Docking Studies)
 To Monitor Reaction Path

30. Applications
 To Calculate Frequencies
⇦IR Spectra by Experiment
⇦ IR Spectra by MM

31. Applications

32. Applications

33.  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.

34.  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.