UNIT 1
Molecular Modelling
Experiment Computational Modelling
Chemistry
Chemistry . . .by Experiment
Chemists make useful materials (pharmaceuticals,
polymers, etc.). Typically, they do this by seeking to
establish connections with molecular structure.
Chemistry . . . by Molecular Modeling
The goal is exactly the same as is the procedure. The
difficult step (materials preparation) has been removed.
Molecular models can be introduced into almost any chemistry lecture. They not only boost
the discussion with “pretty pictures”, but more importantly encourage students to see and
think for themselves. They free teachers from the “limits of the chalkboard” and allow
examination and discussion of “real” molecules.
Matters commonly investigated computationally are:
• Molecular geometry: the shapes of molecules–bond lengths, angles and dihedrals.
• 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.
• Chemical reactivity: for example, knowing where the electrons are concentrated
(nucleophilic sites) and where they want to go (electrophilic sites) helps us to predict
where various kinds of reagents will attack a molecule. A particularly useful application
of this is elucidating the likely mode of action of catalysts, which could lead to improved
versions.
• 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.
• 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.
• The physical properties of substances: these depend on the properties of individual
molecules and on how the molecules interact in the bulk material.
The Tools of Computational Chemistry
The main tools available belong to five broad classes:
1. 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 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, C 27H46O)
can be optimized in seconds on an ordinary personal computer.
2. 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 a
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 Schroodinger
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”.
3. Semiempirical calculations are, like ab initio, based on the Schrodinger equation.
However, more approximations are made in solving it, and the very demanding 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
experimental or, nowadays, high-level theoretical 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 (or high-level theoretical) values (empirical means experimental).
Semiempirical calculations are slower than molecular mechanics but much faster than ab
initio calculations. Semiempirical calculations take perhaps roughly 100 times as long as
molecular mechanics calculations, and ab initio calculations can take roughly 100–1000 times
as long as semiempirical.
4. Density functional theory calculations (often called DFT calculations, a functional is a
mathematical entity related to a function.) are, like ab initio and semiempirical calculations,
based on the Schrodinger equation. However, unlike the other two methods, DFT does not
calculate a wavefunction, but rather derives the electron distribution (electron density
function) directly. Density functional calculations are usually faster than ab initio, but slower
than semiempirical.
5. Molecular Dynamics calculations apply the laws of motion to molecules, which change
shape or move under the influence of a forcefield. 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 protein molecule.
Electronic structure methods
Based on Schrödinger’s Equation: Hψ = Eψ
The Schrödinger equation is the basis of quantum mechanics and gives a complete
description of the electronic structure of a molecule.
Hψ = Eψ Ψ is f(x,y,z)
A set of spatial distributions
H is energy operator which describes
describing the probability of
the kinetic and potential energy of an
finding electrons (orbitals).
electron in field of nuclei and other
electrons.
H= Ek + Ep A single atom has AOs.
P2 Molecules have MOs.
Ek
2m
p is the momentum and m is the mass of the electron
1
E p kx2
2
k is constant and x is the direction of electron E = sum of the energies of the orbitals, which
may contain 1, or at most 2, electrons.
Schrodinger wave equation is a differential equation
Solutions of this equation give the wave function
Density Functional Theory.
Background:
1964: Hohenberg-Kohn paper proving existence of exact DF.
1965: Kohn-Sham scheme introduced
1970s and early 80s: DFT becomes useful.
1988: Becke and LYP functionals. DFT useful for some chemistry.
1998: Nobel prize awarded to Walter Kohn and John Pople in
chemistry for development of DFT.
The Nobel Prize in Chemistry 1998 was divided
equally between Walter Kohn "for his development
of the density-functional theory" and John A. Pople
"for his development of computational methods in
quantum chemistry".
Summary
• Very large molecules are often studied only with molecular mechanics, because
other methods (quantum mechanical methods, based on the Schrodinger equation: semi
empirical, ab initio and DFT) would take too long.
• Novel molecules, with unusual structures, are best investigated with ab initio or possibly
DFT calculations, since the parameterization inherent in MM or semiempirical methods
makes them unreliable for molecules that are very different from those used in the
parameterization.
• Calculations on the structures of large molecules like proteins or DNA are usually done
with molecular mechanics. The conformational motions of these large biomolecules can be
studied with molecular dynamics utilizing a molecular mechanics forcefield; molecular
motions including bond-breaking and -making can be studied with molecular dynamics
utilizing semiempirical, ab initio or density functional methods.
Lecture ends here…
