Molecular Dynamics & Monte Carlo Simulation

BY: R.V. Praveen Kumar 110602014 Dept., Pharmaceutical chemistry 1 MCOPS, Manipal

Contents
Why simulation required Molecular Dynamics Methodology Monte Carlo Simulation Methodology MD or MCS

Why Simulate Motion???

Predict structure Understand interactions Understand properties Learn about normal modes of vibration Design of bio-nano materials Experiment on what cannot be studied experimentally Obtain a movie of the interacting molecules

Scale in Simulations
mesoscale Monte Carlo continuum

10-6 S 10-8 S 10-12 S

Hy = Ey quantum chemistry

molecular dynamics exp(-DE/kT) F = MA

domain

10-10 M 10-8 M 10-6 M Length Scale

10-4 M

Molecular Dynamics (MD)

A computer simulation technique where the time evolution of a set of interacting atoms is followed by integrating their equations of motion. The trajectories of molecules and atoms are determined by numerically solving the Newton's In the field of motion for astudy of the causes of equations of physics, the system of interacting motion andwhere forces between the particles particles, changes in motion and potential energy are defined by molecular mechanics force fields.
A force field refers to the form and parameters of mathematical functions used to describe the potential energy of a system of particles (typically molecules and atoms).

The Energy Model

Proposed by Linus Pauling in the 1930s Bond angles and lengths are almost always the same Energy model broken up into two parts:
Covalent terms
Bond distances Bond angles Dihedral angles

Non-covalent terms
Forces at a distance between all non-bonded atoms.
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The Energy Equation

Energy = Stretching Energy + Bending Energy + Torsion Energy + Non-Bonded Interaction Energy These equations together with the data (parameters) required to describe the behavior of different kinds of atoms and bonds, is called a Force Field.

Bond Stretching Energy

kb is the spring constant of the bond.

r0 is the bond length at equilibrium.

Unique kb and r0 assigned for each bond pair, i.e. C-C, O-H
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Bending Energy

k is the spring constant of the bend. 0 is the bond length at equilibrium.

Unique parameters for angle bending are assigned to each bonded triplet of atoms based on their types (e.g. C-C-C, C-O-C, CC-H, etc.)

Torsion Energy

A controls the amplitude of the curve n controls its periodicity shifts the entire curve along the rotation angle axis ().

The parameters are determined from curve fitting.

Unique parameters for torsional rotation are assigned to each bonded quartet of atoms based on their types (e.g. C-C-CC, C-O-C-N, H-C-C-H, etc.)

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Non-bonded Energy

A determines the degree the attractiveness B determines the degree of repulsion q is the charge

A determines the degree the attractiveness

B determines the degree of repulsion q is the charge
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History
The first paper reporting a MD simulation was written by Alder & Wainwright in 1957. The purpose of this paper was to investigate the phase diagram of a hard sphere system, and in particular the solid and liquid regions. The calculations were performed on a UNIVAC and on an IBM 704. The article Dynamics of radiation damage by J.B. Gibson, A.N. Goland, M. Milgram and G.H. Vineyard appeared in 1960, is probably the first example of a MD calculations with a continuous potential based on a finite difference time integration method. The calculations were performed on IBM 704.
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 Aneesur Rahman (well known pioneer of MD) in his famous 1964 paper Correlations in the motion of atoms in liquid argon, he studied a number of properties of liquid Ar, using the Lennard-Jones potential on a system containing 864 atoms and a CDC 3600. Loup Verlet in 1967 calculated the phase diagram of argon using the L-J potentials, and computed correlation functions to test theories of the liquid state. Verlet time It is a mathematically simple model that approximates integration algorithm was used. atoms or the interaction between a pair of neutral
molecules.

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What is MD???
It is a deterministic approach and a multidisciplinary field. Its laws and theories stem from mathematics, physics and chemistry. MD employs algorithms from computer science and information theory. It is a specialized discipline of molecular modeling and computer simulation based on statistical mechanics; the main justification of the MD method is that statistical ensemble averages are equal to time averages of the system, known as the ergodic hypothesis. MD has also been termed "statistical mechanics by numbers" and "Laplace's vision of Newtonian mechanics" of predicting the future by animating nature's forces and allowing insight into molecular motion on an atomic scale.
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Methodology
From atom positions, velocities, and accelerations, calculate atom positions and velocities at the next time step. Integrating these infinitesimal steps yields the trajectory of the system for any desired time range. There are efficient methods for integrating these elementary steps with Verlet and leapfrog algorithms being the most commonly used.
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MD algorithm
Initialize system

{r(t+Dt), v(t+Dt)}

{r(t), v(t)}

Ensure particles do not overlap in initial positions (can use lattice) Randomly assign velocities.

Move and integrate.

Leapfrog algorithm

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Types of MD

Constant- Temperature

Constant-Pressure

For carrying out MD at constant pressure are The current temperatureT(t) at time the same exactly equal the the based on point t is principles as to constant desired reference temperature To. This can be achieved the rescaling the by role of temperature scheme with 1/2 the velocities at each MD time step by a factor by the pressure and the role temperature played [To/T(t)] , where the temperature T(t) is defined in terms of the kinetic played by the atomic of the atomic velocities energy through equipartition. The number of degrees of freedom in the system is Ndf. positions. 1 Ekin(t)= =1 2 (t) = Ndf kbT(t)
2
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Applications
Used to are much molecular motion. Computersstudy internal cheaper than big, expensive laboratories, hence simulation can and does save A promising tools for helping to elucidate the industry significant expenseproteins. structure of medium sized in the formulation of new and novel materialsused pharmaceuticals. studying The most widely and theoretical tools for the molecular behaviour of fluids and solids. From the time averages of phase variables in a microscopic system, such as energy, pressure, shear stresses, etc., one may calculate the material properties of a corresponding macroscopic systems, e.g., cohesive energies of solids, surface tensions of liquid interfaces, bulk and shear viscosities of fluids, thermal conductivities, etc.
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Some reported MD Simulations

First macromolecular MD simulation published (1977, Size: 500 atoms, Simulation Time: 9.2 ps=0.0092 ns, Program: CHARMM precursor) Protein: Bovine Pancreatic Trypsine Inhibitor. This is one of the best studied proteins in terms of folding and kinetics. Its simulation published in Nature magazine paved the way for understanding protein motion as essential in function and not just accessory. MD is the standard method to treat collision cascades in the heat spike regime, i.e. the effects that energetic neutron and ion irradiation have on solids an solid surfaces.
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MD Algorithms
Short-range interaction algorithms Long-range Integrators interaction algorithms Parallelization strategies Cell lists decomposition method (Distribution Ewald summation Domain Verlet-Stoermer integration Verlet list data for parallel computing) Particle Mesh Ewald (PME) of system Runge-Kutta integration Bonded interactions Particle-Particle Particle Mesh P3M Beeman's algorithm Constraint algorithms (for constrained systems) Symplectic integrator

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Major Software's
Auto Dock suite of automated NAMD (classical, parallelization docking to thousands of with up tools, CPU's, (classical, implicit AbaloneGPU accelerated) water, GPU accelerated) ORAC (classical) PWscf (DFT) ABINIT (DFT) SIESTA (DFT) Tremolo-X (classical, AMBER (classical) parallelization with up to Ascalaph Designer (classical) thousands of CPU's) CASTEP (DFT) VASP (DFT) TINKER (classical) CP2K (DFT) XMD (DFT) CPMD(classical) CHARMM (classical, the pioneer in MD simulation, extensive analysis tools) HOOMD-blue (classical, GPU accelerated) MacroModel (classical) Desmond (classical, parallelization with up to thousands of CPU's) GPAW (DFT, large-scale parallelisation) GPIUTMD (classical, GPU acc elerated) GROMACS (classical, GPU ac celerated) GROMOS (classical) LAMMPS (classical, largescale with spatialdecomposition of simulation domain for parallelism) MDynaMix (classical, parallel) MOSCITO (classical) 21

Monte Carlo Simulation

A problem solving technique used to approximate the probability of certain outcomes by running multiple trials called simulation, using random numbers. The Monte Carlo was coined in the 1940s by John von Neumann, Stanislaw Ulam and Nicholas Metropolis. It depends on statistical mechanics rather than molecular dynamics.
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 It is also a conformational analysis method like MD. It employs a Markov chain procedure in order to determine a new state for a system from a previous one. The avoidance of dynamics restricts the Mathematical studies of static quantities only, method to systems that undergoes transitions from one state to another in a chain like manner. but the freedom to choose moves makes the method flexible.
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Methodology
The Monte Carlo (MC) simulation procedure by which a (canonical) ensemble is produced consists of the following steps. 2. The newly starting configuration rs a s+1 is 1. Given a generated configuration r new configuration rs+1 = rs + r is the basis of either accepted or rejected on generated by random displacement of one the change E an energy criterion involving(or more) atoms. The random displacements r should be such = V(rs+1) - V(rs) of the potential energy with that in the limit of a large number of successive respect to the previous Configuration. The displacements the available Cartesian space of new configuration is accepted whendoes<not all atoms is uniformly sampled. This E 0, or if E > 0 when e-E/kBT > R, where R is a mean that the actual sampling must be carried random number taken from a uniform out in Cartesian space.

distribution over the interval (0,l).

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 Upon acceptance, the new configuration is counted and used as a starting point for the next random displacement. If the criteria are not met, the new configuration rs+1, is rejected. This implies that the previous configuration rs is counted again and used as a starting point for another random displacement.

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 This procedure will generate a Boltzmann ensemble. We consider two configurations r1 and r2 with energies E1 = V(r1) < V(r2) = E2 The probability of stepping from configuration r2 to r1 equals 1, the reverse step has a probability exp( - (E2 E1)/kBT). When the populations p1 and p2 of the two configurations are in equilibrium, one has detailed balance conditions.
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P2 = p1 (21)/ Each configuration occurs with a probability proportional to its Boltzmann factor. The advantage of this (Metropolis) Monte Carlo or Boltzmann sampling over random sampling is that most sampled configurations are relevant (low energy), while with random sampling much computational effort is likely to be spent on irrelevant (high energy) configurations. In order to obtain high computational efficiency, one would like to combine a large (random) step size with a high acceptance ratio. This is possible when applying MC techniques to simulate simple atomic or molecular liquids. 27

 However, for complex systems involving many covalently bound atoms, a reasonable acceptance ratio can only be obtained for very small step size. This is due to the fact that a random displacement will inevitably generate a very high bond energy of the bonds of the displaced atom. This makes MC methods rather inefficient for (macro)molecular systems.

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MCS in Chemistry and Biochemistry

Very valuable in understanding the structure and properties of liquids.
For example, MCS with accurate energy potentials can estimate liquid densities and heats of vaporization with few percent accuracy. It can provide information about the structure of hydration shells around solutes and allow to estimate how different solvents alter the energy profiles in chemical reactions.

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MD or MCS ???
The choice largely determined by the phenomenon under investigation. For a simulation of a gas or other low density systems, Monte Carlo simulations are preferable. There can be large energy barriers to torsional rotations in molecules which can lead to molecules being trapped in a few low energy conformations in a MD simulation, leading to poor conformational sampling. In contrast, the random moves in a MC simulation can easily lead to barrier crossings.
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MD or MCS
For a liquid simulation MD becomes favourable. Here molecular collisions exchange energy between molecules, enabling barrier crossings, improving the ability of MD to sample conformations. For a MC simulation, there is a large probability of selecting random moves for which two or more molecules overlap leading to large number of rejected moves and a decrease in efficiency of sampling.
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Specific case were only MD is preferred

Determination of transport properties such as viscosity coefficients, as MC lacks an objective definition of time

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Specific case were only MC is preferred

MC can be used for simulations with varying particle numbers by adding moves for the creation and destruction of particles.

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References
Fundamentals of medical chemistry by Garet Thomas, page no: 106-120. Burgers medicinal chemistry and Drug discovery by Donald J. Abraham., Vol,. 1. page no. 63-64 Computer Simulation of Molecular Dynamics: Methodology, Applications, and Perspectives in Chemistry By Wilfred E van Gunsteren * and Herman J. C. Berendsen http://www.chem.ucsb.edu/~kalju/MonteCarlo_4.html http://cmt.dur.ac.uk/sjc/thesis_dlc/node58.html http://en.wikipedia.org/wiki/Monte_Carlo_method
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