Molecular Dynamics

For any molecule, Provides the detailed information on the fluctuations and changes in conformational space due to molecular motion, in a given time Mimics how a molecular system actually explores its conformational space.
However, search is confined to those states which can be attained at the temperature where such a study is being carried out.

Suited also for larger molecular systems such as proteins or periodic systems.

MD is Used to investigate
Structure, Dynamics and Thermodynamics of biological molecules and their complexes Structures from x-ray crystallography and NMR experiments

MD study consists of integrating molecular motion governed by Newton's laws of motion

In MD, successive configurations of the system are generated by integrating Newtons laws of motion.
The result is a trajectory that specifies how the positions and velocities of the atoms in the system vary with time.

Newtons laws of motion

A body continues to move in a straight line at a constant velocity unless any force acts upon it. Force depends on the rate of change of momentum. For every action there is an equal and opposite reaction. The trajectories are obtained by solving the differential equations embodied in Newtons 2nd law (F=ma).

d 2 xi Fxi 2 dt mi
This equation describes the motion of a particle of mass mi along one coordinate xi with Fxi being the force on the particle in that direction.

Newtons equation of motion is given by

Fi = miai where Fi is the force exerted on particle i, mi is the mass and ai is the acceleration.

The force can also be expressed as the gradient of the potential energy, Fi = - iV, where V is the potential energy of the system.

Combining these two equations yield

Newtons equation of motion can then relate the derivative of the potential energy to the changes in position as a function of time.

Newtons Second Law of motion: a simple application

Taking the simple case where the acceleration is constant,

we obtain an expression for the velocity after integration

and since we can once again integrate to obtain Combining this equation with the expression for the velocity, we obtain the following relation which gives the value of x at time t as a function of the acceleration, a, the initial position, x0 , and the initial velocity, v0..

The acceleration is given as the derivative of the potential energy with respect to the position, r,

Molecular Dynamics
1.Select a target temperature and construct a set of velocities. Kinetic Energy; U = 3/2 kT = 3/2 mv2 T = mv2 / k 2. Allow atoms to move for one time step. r(t + t) = r(t) + v t 3. Calculate the force on the atoms (forcefield) 4. Calculate the acceleration : F = m a 5. Calculate the velocity at t = t + t/2 v(t + t/2) = v(t + t/2) + a t 6. Calculate the position after the next time step. r(t + t) = r(t) + v t Repeat for as many time steps as desired.

The Process
Maxwell-Boltzmann distribution which describes the distribution of any form of energy among interacting molecules as a function of temperature.

Comments on MD Equilibration
Prepare the system to reach the most probable configuration consistent with the target T and P.

When a system is large - long time to equilibrate - vast conformational space it has to search
The contour of the energy surface is another factor to consider

 If energy barriers between various LM and the GM are high, barrier crossing is difficult and may take longer. How to judge whether a system has equilibrated Plot the various thermodynamic qualities, such as E, T and P etc.. vs Time. When equilibration has been achieved, these quantities fluctuate around their averages which remain constant over time.
LM local minima GM global minima

Applications
During MD simulations, system undergoes conformational and momentum changes such that different parts of the phase space accessible to the molecules can be explored Most important use is conformational search capability

By providing several mechanisms for controlling the temperature and pressure of simulated systems, MD also allows you to generate statistical ensembles from which various energetic, thermodynamic, structural and dynamic properties can be calculated

Ensemble
An ensemble is a collection of all possible systems which have different microscopic states but have an identical macroscopic or thermodynamic state. There exist different ensembles with different characteristics.

Start from:

Molecular energy levels and boltzmann distribution

E = nii
E=total energy of the system ni= molecules in a state of energy i

Find the most probable population of the state of energy i which is ni*= e(-i)

Find and using N = ni* = ee-i

ni*/N = e-i / eI
ni* = next conformational minima

q = e-i is called molecular partition function. This sum is over different states of the individual molecules q = gje-i
g = ground electronic state

= 1/kT

This represents different energy levels of the molecule.

alpha and beta are the different energy minimas

Example for translational partition function,

Think of a system, a large reservoir, should be in thermal contact, but as constituting an isolated unit, and if you are reproducing this many times becomes an ensemble.

Statistical Ensembles
1. Constant energy, Constant Volume (NVE), also known as the microcanonical ensemble. 2. Constant temperature, constant volume (NVT) this is the most common dynamics system, also known as the canonical ensemble 3. Constant temperature, constant pressure (NPT) 4. Constant temperature, constant stress (NST) 5. Constant pressure, constant enthalphy (NPH) In all these ensembles, the number of particles is conserved

NVE Ensemble
This is a useful ensemble, If you are interested in exploring the constant-energy surface of the conformational space or for other reasons do not want the perturbation introduced by T- and P-bath coupling

Constant energy simulations are not recommended for

equilibration of dynamics, because without the energy flow facilitated by the temperature control methods, the desired temperature cannot be achieved. However, this can be done during the data collection phase only

NVT Ensemble
This is the appropriate choice when conformational searches of molecules are carried out in vacuum without periodic boundary conditions. The ensemble is obtained by controlling the T through

Direct T scaling during the initialization stage and by T-bath coupling during the data collection phase

NPT Ensemble
The ensemble NPT allows control over both the T and P. The unit cell vectors are allowed to change, and the P is adjusted by adjusting the V.

This is the ensemble of choice when the correct P, V, and densities are important in the simulation.
This ensemble can also be used during equilibration to achieve the desired T and P before changing to the NVE ensemble when data collection starts.

NST Ensemble
This is an extension of the NPT. In addition to the hydrostatic pressure which is applied isotropically, constant-stress ensemble allows you to control the xx, yy, zz, xy, yz and zx components of the stress tensor (sometimes also known as pressure tensor). Particularly useful if you want to study the stress-strain relationship in polymeric or metallic materials.

NPH Ensemble
This ensemble is an analogue of NVE ensemble.
Enthalpy H, which is the sum of E and PV, is constant when the P is kept fixed without any T control.

Dynamic Temperature
Temperature is a state variable that specifies the thermodynamic state of the system This macroscopic quantity is related to the microscopic description of molecular simulations through the K.E., which is calculated from the atomic velocities. The temperature and the distribution of atomic velocities in a system are related through the Maxwell-Boltzmann equation.

1 2 3 mv kT 2 2

continued ..

Dynamic Temperature
Temperature is meaningful only at equilibrium.

The initial velocities are generated so as to maintain a Maxwell-Boltzmann distribution at the desired temperature.
However this distribution does not remain constant as the simulation continues.

This is because during MD, as the minimised structure changes to the equilibrium structure, K.E. changes to P.E. and the T also changes. To maintain the correct T, the computed velocities have to be adjusted appropriately.

The choice of dynamic time step

A key parameter in the integration algorithms is integrating time step t. To make the best use of the computer time, a large time-step (t) should be used.

However, too large a time-step causes instability and inaccuracy in the integration process.
The time-step used depends on the system as well as the integrators.

continued

Simulation Time
The main limitation imposed by the system is the highestfrequency motion that must be considered.

A vibrational period must be split into at least 8-10 segments for molecular systems to satisfy the Verlet assumption that the velocities and accelerations are constant over the timestep used.
In most molecular systems, the highest vibrational frequency is that of C-H bond stretching, whose period is on the order of 10-14 fs. The integration time-step should therefore be about 1 fs.

Nonbond cutoffs
The most computationally intensive part of a MM P.E. calculation is the calculation of the nonbond interactions. To limit this calculation, a nonbond cutoff is often used. The nonbond vander Waals and electrostatic interactions between atoms in groups more than a certain distance are not included. During a MD, the neighbor list is periodically checked to see if groups have moved into or out of the potential cutoff distance.
MM-molecular mechanics

Dynamics
Limitations: - Quality of the forcefield The quality of the results of a MM calculation depends upon how well the force-field models reality. - Size and Time Atomic simulations can be performed only on systems of a few tenths of angstroms on the length scale and for a few nanosec on the time scale

- Conformational freedom of molecules

MM-molecular mechanics