Molecular Mechanics
Calculation of energy of atoms, force on atoms
& their resulting motion
Newtonian mechanics
Use
Improve trial structure by eliminating distortion,
steric clashes, finding better conformation.
Study motion of molecule eg rigid body motion of
domains etc
Potential Energy
Components
(1) bond length
Bonds behave like spring with equilibrium bond
length depending on bond type. Increase or decrease
from equilibrium length requires higher energy.
Potential Energy
(2) bond angle
Bond angles have equilibrium value eg 108 for HC-H
Behave as if sprung.
Increase or decrease in angle requires higher
energy.
Potential Energy
(3) torsion angle
Rotation can occur about single bond in A-B-C-D but
energy depends on torsion angle (angle between CD &
AB viewed along BC). Staggered conformations (angle
+60, -60 or 180 are preferred).
Potential Energy
(4) van der Waals interactions
Interactions between atoms not near neighbours
expressed by Lennard-Jones potential.
Very high repulsive force if atoms closer than sum of
van der Waals radii.
Attractive force if distance greater. Because of strong
distance dependence, van der Waals interactions
become negligible at distances over 15 A
Potential Energy
(5) Electrostatic interactions
All atoms have partial charge eg in C=O C has partial positive
charge, O atom partial negative charge.
Two atoms that have the same charge repel one another, those
with unlike charge attract.
Dielectric constant to use in uncertain.
Dipoles. In many cases molecules made of neutral groups.
Two adjacent atoms have opposite charges & behave like
dipole. In this case the potential energy falls off as 1/r3
Electrostatic energy falls off much less quickly than for van
der Waals interactions and may not be negligible even at 30 A.
Potential Energy
Cut off
Calculation of interaction between non-bonded
atoms takes most of the computation
This is lessened if a cut off distance is applied assumed that above this distance the
interaction between two atoms is negligible
Potential Energy
Potential Energy is given by the sum of these contributions:
Hydrogen bonds are usually supposed to arise by
electrostatic interactions but occasionally a small extra
term is added.
Potential
To reduce the complexity of calculations atoms
grouped into types (potential atom types)
eg all Hs in methane are the same & similar to H
s in ethane
the C atoms in ethane are different from those in
ethylene
the O in a C=O group is different from the O in a
C-O-H group. But O atoms in alcohols are
similar.
Force fields
A force field is the description of how potential
energy depends on parameters
Several force fields are available
AMBER used for proteins and nucleic acids
cvff (consistent valence force field)
Force fields differ:
in the precise form of the equations
in values of the constants for each atom type
Energy minimisation
Calculation of how atoms should move to minimise TOTAL
potential energy
At minimum, forces on every
atom are zero.
Optimising structure to remove strain & steric clashes
However, in general finds local rather than global minimum.
Energy barriers are not overcome even if much lower
energy state is possible ie structures may be locked in.
Hence not useful as a search strategy.
Energy minimisation
Potential energy depends on many parameters
Problem of finding minimum value of a function with >1
parameters. Know value of
function at several points.
Grid search is computationally
not feasible
Methods
Steepest descents
Conjugate gradients
Energy minimisation
Example 1 Hexabenzene ring has been made in
InsightII. The strain is small. This will be energy
minimised.
Example 2 Pentabenzene ring has been made in
InsightII. This has a large strain which will be reduced
on energy minimisation.
Energy minimisation
Example 3 Energy minimisation of ADP+Pi at the
active site of myosin. The crystal structure used is the
motor domain complexed with ADP+vanadate and the
vanadate has been replaced by Pi. What happens to the
stereochemistry of the Pi?
Example 4 Energy minimisation of GTP at the active
site of myosin. ATP has been replaced by GTP. How
does the guanine base fit?
Molecular dynamics
Energy minimisation gives local minimum, not necessarily
global minimum.
Give molecule thermal energy so can explore conformational
space & overcome energy barriers.
Give atoms initial velocity random value + direction. Scale
velocities so total kinetic energy =3/2kT * number atoms
Solve equation of motion to work out position of atoms at 1 fs.
Molecular dynamics
Higher the temperature the greater and faster
the motion & more of conformational space
sampled.
Use
(a) to overcome energy barriers to find better
structure
(b) explore motion
Molecular Dynamics
Example 1 Molecular dynamics simulation of
pentabenzene
Molecular Dynamics
Example 2 Molecular dynamics simulation showing
movement of ATP, Mg, side chains and water in the
active site of myosin.
Water
A protein is surrounded with water molecules. Side
chains on surface of interact with water. Modelling a
protein without water is not realistic.
Ideally surround protein with large bath of water. But
computationally intensive & large number of
combinations of water positions & interactions
In practice surround protein with thin layer of water.
