Computational chemistry is the use of computers to
solve the equations of a theory or model for the
properties of a chemical system.
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Three “Pillars” of Scientific Investigation
⮚ Experiment
⮚ Theory (analytical equations)
⮚ Computational Simulation
⮚ (“theoretical experiments”)
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⮚ Simulation is becoming a third pillar of science, along
with theory and experiment.
⮚ Using theory, we develop models: simplified
representations of physical systems.
⮚ We test the accuracy of these models in experiment, and
use simulation to help refine this feedback loop.
⮚ Anything that can be measured can be simulated,
including properties related to energetics, structures,
and spectra of chemical systems.
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The Nobel Prize in Chemistry 1998
John A. Pople Walter Kohn
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".
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2013 Nobel Prize In Chemistry
"for the development of multiscale models for complex chemical systems”
• Martin Karplus, Université de Strasbourg, France, and Harvard University,
Cambridge, MA, USA
• Michael Levitt, Stanford University, Los Angeles, CA, USA
• Arieh Warshel, University of Southern California (USC), CA, USA 5
Computational Chemistry
WHY
do theoretical calculations?
WHAT
do we calculate?
HOW
are the calculations carried out?
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Theoretical/Computational
Chemistry
Classical Mechanics Quantum Mechanics
Sir Isaac Newton Erwin Schrödinger
(1642 - 1727) (1887 - 1961)
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Overview of computational methodologies
Quantum Mechanics (QM) Classical Mechanics (CM)
Molecular Mechanics (MM)
Molecular Dynamics (MD)
Ab initio methods Semi-empirical
methods
Density functional theory (DFT)
Schrödinger Equation
• H is the quantum mechanical Hamiltonian for the
system (an operator containing derivatives)
• E is the energy of the system
• Ψ is the wave function (contains everything we are
allowed to know about the system)
• |Ψ|2 is the probability distribution of the particles
Ab-initio methods
o The term "Ab Initio" is Latin for "from the beginning".
Computations of this type are derived directly from theoretical
principles, with no inclusion of experimental data.
o Mathematical approximations are usually a simple functional form
for a an approximate solution to A wave function! (The Shrödinger
Equation).
o These methods try to compute an accurate as possible many
electron wavefunction which then automatically leads to an
accurate total energy.
o Accuracy can be systematically improved.
Semi-empirical methods
o It uses approximations from empirical (experimental) data to
provide the input into the quantum chemical models.
o Accuracy depends on parameterization.
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o DFT allows getting information about the energy, the structure and
the molecular properties of molecules at lower costs. It goes with
electron density instead of wave function. Accuracy varies with
functionals, however, there is no systematical way to improve the
accuracy.
o Molecular mechanics uses classical physics and empirical or semi-
empirical (predetermined) force fields to explain and interpret the
behavior of atoms and molecules. Generally not very accurate.
o Molecular dynamics is a computer simulation technique that allows one
to predict the time evolution of a system of interacting particles (atoms,
molecules, etc.)
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Doing Chemistry with Computers
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Using computational chemistry software you can in particular perform:
o Electronic structure predictions
o Geometry optimizations or energy minimizations
o Conformational analysis and potential energy surfaces (PES)
o Frequency calculations
o Finding transition structures and reaction paths
o Molecular docking: Protein – Protein and Protein-Ligand interactions
o Electron and charge distributions calculations
o Calculations of rate constants for chemical reactions: Chemical
kinetics
o Thermochemistry - heat of reactions, energy of activation, etc.
o Calculation of many other molecular and physical and chemical
properties
o Orbital energy levels and electron density
o Electronic excitation energy 15
Computer Performance
1990 2000 2021
Years
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• Structure of a molecule in general is how atoms are arranged
in the molecule in the three dimensional space.
• Potential energy surface (PES) is a plot of energy with respect
to various internal coordinates of a molecule such as bond
length, bond angle etc.
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• The PES is the energy of a molecule as a function of the positions
(coordinates).
• This energy of a system of two atoms depends on the distance
between them.
• At large distances the energy is zero, meaning “no interaction”.
• The attractive and repulsive effects are balanced at the minimum
point in the curve
Potential energy for nuclear motion in a diatomic molecule
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Potential Energy Surfaces and Mechanism
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Conformational Analysis
⮚ Identification of all possible minimum energy structures
(conformations) of a molecule is called conformational analysis.
⮚ Conformational analysis is an important step in computational
chemistry studies as it is necessary to reduce time spent in the
screening of compounds for properties and activities.
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⮚ The identified conformation could be the local minimum,
global minimum, or any transition state between the
minima.
⮚ Out of the several local minima on the potential energy
surface of a molecule, the lowest energy conformation is
known as the global minimum.
Global minimum
Local minima
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Local minimum Local minimum
Global minimum
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Ethane Conformations
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Ramachandran plot: Peptide and Protein systems
• In a polypeptide, the main chain N-C and C-C bonds relatively are free to rotate. These
rotations are represented by the torsion angles phi and psi, respectively.
• G N Ramachandran used computer models of small polypeptides to systematically vary
phi and psi with the objective of finding stable conformations.
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Geometry optimization
Or
Energy Minimization
To Find
• Minimum energy geometry
• Lowest energy structure
• Most stable conformation
• Many problems in computational chemistry (and scientific
computing in general!) are optimization problems
• Finding the “stationary points” in multidimensional system
– Difficult Job
Why do we need the stable geometry?
Geometry optimization
⮚ The most stable geometry is the one which yields
minimum energy
⮚ Objective of geometry optimization is to find an atomic
arrangement(geometry) which makes the molecule most
stable
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Methods of Optimization
Energy only:
• Simple methods
Energy and first derivatives (forces)
• Steepest descents (poor convergence)
• Conjugate gradients (retains information)
• Approximate Hessian update
Energy, first and second derivatives
• Newton-Raphson
• Broyden (BFGS) updating of Hessian (reduces inversions)
• Rational Function Optimization (for transition states)