Molecular Dynamics

Molecular Dynamics are used to investigate the structure, dynamics and thermodynamics of biological molecules and their complexes
Protein stability Conformational changes Protein folding Molecular recognition: proteins, DNA, membranes, complexes Ion transport in biological systems

The molecular dynamics method was first introduced by Alder and Wainwright in the late 1950's (Alder and Wainwright, 1957,1959) to study the interactions of hard spheres
The first molecular dynamics simulation of a realistic system was done by Rahman and Stillinger in their simulation of liquid water in 1974 (Stillinger and Rahman, 1974). The first protein simulations appeared in 1977 with the simulation of the bovine pancreatic trypsin inhibitor (BPTI) (McCammon, et al, 1977).

The molecular dynamics simulation method is based on Newtons second law or the equation of motion, F=ma, where F is the force exerted on the particle, m is its mass and a is its acceleration From a knowledge of the force on each atom, it is possible to determine the acceleration of each atom in the system Integration of the equations of motion then yields a trajectory that describes the positions, velocities and accelerations of the particles as they vary with time. From this trajectory, the average values of properties can be determined The method is deterministic; once the positions and velocities of each atom are known, the state of the system can be predicted at any time in the future or the past

Newtons equation of motion is given by

where Fi is the force exerted on particle i, mi is the mass of particle i and ai is the acceleration of particle i. The force can also be expressed as the gradient of the potential energy,

Integration Algorithms The potential energy is a function of the atomic positions (3N) of all the atoms in the system. Due to the complicated nature of this function, there is no analytical solution to the equations of motion; they must be solved numerically. Numerous numerical algorithms have been developed for integrating the equations of motion. Verlet algorithm Leap-frog algorithm Velocity Verlet Beemans algorithm Important: In choosing which algorithm to use, one should consider the following criteria: The algorithm should conserve energy and momentum. It should be computationally efficient It should permit a long time step for integration.

Integration Algorithms All the integration algorithms assume the positions, velocities and accelerations can be approximated by a Taylor series expansion:

Where r is the position, v is the velocity (the first derivative with respect to time), a is the acceleration (the second derivative with respect to time), etc.

To derive the Verlet algorithm we can write

Summing these two equations, one obtains

The Verlet algorithm uses positions and accelerations at time t and the positions from time t-dt to calculate new positions at time t+dt. The Verlet algorithm uses no explicit velocities.

The Velocity Verlet algorithm This algorithm yields positions, velocities and accelerations at time t. There is no compromise on precision.

The Leap-frog algorithm

In this algorithm, the velocities are first calculated at time t+1/2dt; these are used to calculate the positions, r, at time t+dt. In this way, the velocities leap over the positions, then the positions leap over the velocities. The advantage of this algorithm is that the velocities are explicitly calculated, however, the disadvantage is that they are not calculated at the same time as the positions. The velocities at time t can be approximated by the relationship:

Beemans algorithm
This algorithm is closely related to the Verlet algorithm

The advantage of this algorithm is that it provides a more accurate expression for the velocities and better energy conservation. The disadvantage is that the more complex expressions make the calculation more expensive.

Conformation Searching
Systematic Searching Tree Search Random Searching Genetic algorithms

PHARMACOPHORE
Asp25 Gly27
O Donor O

Geometric arrangement of types of functional groups that are required for activity at the active site.

O Donor

6.9

6.0 5.2 6.3 Hydrophobic H3C CH3 CH C H2 10.4 Acceptor H N

Ile50

Receptor Analysis
Asp25 Gly27 Acceptor or Anion
O O

Asp25 Gly27
6.9 O 12.2 8.8 9.6 O

Acceptor

Donor Hydrophobic
H3C CH3 CH C H2 H N H3C

6.3 CH3 CH C H2

H N

Ile50

Ile50

Identify functional group

Determine distances
O

Asp25 Asp25 O Gly27 Gly27 Acceptor Acceptor O O or Anion or Anion

Asp25 Asp25 Gly27 Gly27

6.9 6.9 O

O O

O O

O Acceptor Acceptor

Donor Donor

6.9 6.9

Donor Donor
6.06.0

Donor Donor Acceptor Acceptor Hydrophobic Hydrophobic CH3 Hydrophobic Hydrophobic

Ile50Ile50
H3 C H3 C C H2

Donor Donor

9.6 12.2 9.6 12.2

CH3

H N

Donor Hydrophobic Donor Hydrophobic

H N

10.4 10.4 8.8 8.8 5.2 5.2 Acceptor Acceptor 6.3 6.3 6.3 CH 6.3 CH3 3
H H N N

CH CH C H2

Ile50 Ile50

CH CH H3CH3C C C H2 H 2

Final Pharmacophore
6.9

Donor
6.0 10.4

Donor
5.2 6.3

Acceptor

Hydrophobic
Many molecules could fulfill the above pharmacophore
Identify such molecules via database screening or de novo design

De novo Ligand Design

De novo Ligand Design

De novo Ligand Design

De novo Ligand Design

De novo Ligand Design

+
Ligand Receptor
Docking software

The complex quality is evaluated by the score.

Ligand receptor complex

Starting compound

Final compound

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