Introduction

One of the principal tools in the theoretical study of biological molecules is the method of 
molecular dynamics simulations (MD). This computational method calculates the time 
dependent   behavior   of   a   molecular   system.   MD   simulations   have   provided   detailed 
information   on   the   fluctuations   and   conformational   changes   of   proteins   and   nucleic 
acids.   These methods are now routinely used to investigate the structure, dynamics and 
thermodynamics of biological molecules and their complexes. They are also used in the 
determination of structures from x­ray crystallography and from NMR experiments.

Biological   molecules   exhibit   a   wide   range   of   time   scales   over 

which specific processes occur; for example

• Local Motions (0.01 to 5 Å, 10­15 to 10­1 s)
o Atomic fluctuations
o Sidechain Motions
o Loop Motions
• Rigid Body Motions (1 to 10Å, 10­9 to 1s)
o Helix Motions
o Domain Motions (hinge bending)
o Subunit motions
• Large­Scale Motions (> 5Å, 10­7 to 104 s)
o Helix coil transitions
o Dissociation/Association

o Folding and Unfolding

An overview of the theoretical foundations of classical molecular dynamics simulations, to 
discuss   some   practical   aspects   of   the   method   and   to   provide   several   specific   applications 
within the framework of the CHARMM program. Although the applications will be presented 
in   the   framework   of   the   CHARMM   program,   the   concepts   are   general   and   applied   by   a 
number of different molecular dynamics simulation programs. The CHARMM program is a 
research program developed at Harvard University for the energy minimization and dynamics 
simulation of proteins, nucleic acids and lipids in vacuum, solution or crystal environments 
(Harvard CHARMM Web Page http://yuri.harvard.edu/).

Section   I   of   this   course   will   focus   on   the   fundamental   theory   followed   by   a   brief 
discussion of classical mechanics.  In section II, the potential energy function and some 
related   topics   will   be   presented.   Section   III   will   discuss   some   practical   aspects   of 
molecular dynamics simulations and some basic analysis. The remaining sections will 
present the CHARMM program and provide some tutorials to introduce the user to the 
program. This course will concentrate on the classical simulation methods (i.e., the most 
common) that have contributed significantly to our understanding of biological systems. 

Molecular   dynamics   simulations   permit   the   study   of   complex, 

dynamic processes that occur in biological systems. These include, 
for example,

• Protein stability
• Conformational changes
• Protein folding
• Molecular   recognition:   proteins,   DNA,   membranes, 
complexes
• Ion transport in biological systems

and provide the mean to carry out the following studies,

• Drug Design

• Structure determination: X­ray and NMR

Historical Background

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. 
Many important insights concerning the behavior of simple liquids emerged from their 
studies.   The   next   major   advance   was   in   1964,   when   Rahman   carried   out   the   first 
simulation using a realistic potential for liquid argon (Rahman, 1964). 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). Today in the literature, one routinely finds 
molecular dynamics simulations of solvated proteins, protein­DNA complexes as well as 
lipid  systems   addressing   a variety  of issues  including  the  thermodynamics   of  ligand 
binding   and  the   folding  of  small  proteins.   The  number   of  simulation   techniques   has 
greatly expanded; there exist now many specialized techniques for particular problems, 
including mixed quantum mechanical ­ classical simulations, that are being employed to 
study   enzymatic   reactions   in   the   context   of   the   full   protein.   Molecular   dynamics 
simulation   techniques   are   widely   used   in   experimental   procedures   such   as   X­ray 
crystallography and NMR structure determination.

References

Alder, B. J. and Wainwright, T. E. J. Chem. Phys. 27, 1208 
(1957)

Alder, B. J. and Wainwright, T. E.  J. Chem. Phys.  31, 459 

(1959)

Rahman, A. Phys. Rev. A136, 405 (1964)

Stillinger, F. H. and Rahman, A.  J. Chem. Phys.  60, 1545 

(1974)

McCammon, J. A., Gelin, B. R., and Karplus, M.  Nature  
(Lond.) 267, 585 (1977)

3. STATISTICAL MECHANICS

Molecular   dynamics   simulations   generate   information   at   the   microscopic   level, 

including atomic positions and velocities. The conversion of this microscopic information 
to   macroscopic   observables   such   as   pressure,   energy,   heat   capacities,   etc.,   requires 
statistical   mechanics.   Statistical   mechanics   is   fundamental   to   the   study   of   biological 
systems by molecular dynamics simulation. In this section, we provide a brief overview 
of   some   main  topics.  For  more  detailed   information,  refer   to  the   numerous   excellent 
books available on the subject.

INTRODUCTION TO STATISTICAL MECHANICS:

In   a   molecular   dynamics   simulation,   one   often   wishes   to   explore   the   macroscopic 

properties   of   a   system   through   microscopic   simulations,   for   example,   to   calculate 
changes in the binding free energy  of a particular drug candidate, or to examine the 
energetics   and   mechanisms   of   conformational   change.   The   connection   between 
microscopic   simulations   and   macroscopic   properties   is   made   via  statistical   mechanics 
which provides the rigorous mathematical expressions that relate macroscopic properties 
to   the   distribution   and   motion   of   the   atoms   and   molecules   of   the   N­body   system; 
molecular dynamics simulations provide the means to solve the equation of motion of 
the   particles   and   evaluate   these   mathematical   formulas.   With   molecular   dynamics 
simulations,   one   can   study   both   thermodynamic   properties   and/or   time   dependent 
(kinetic) phenomenon.

Reference Textbooks on Statistical Mechanics

D.   McQuarrie,   Statistical   Mechanics   (Harper   &   Row,   New 

York, 1976)

D.   Chandler,   Introduction   to   Modern   Statistical   Mechanics 

(Oxford University Press, New York, 1987)

R. E. Wilde and S. Singh, Statistical Mechanics, Fundamentals 
and Modern Applications (John Wiley & Sons, Inc, New York, 
1998)

  

Statistical mechanics is the branch of physical sciences that studies macroscopic systems 
from a molecular point of view. The goal is to understand and to predict macroscopic 
phenomena   from   the   properties   of   individual   molecules   making   up   the   system.   The 
system could range from a collection of solvent molecules to a solvated protein­DNA 
complex. In order to connect the macroscopic system to the microscopic system, time 
independent   statistical   averages   are   often   introduced.   We   start   this   discussion   by 
introducing a few definitions.

Definitions

The thermodynamic state of a system is usually defined by a small set of parameters, for 
example,   the   temperature,   T,   the   pressure,   P,   and   the   number   of   particles,   N.   Other 
thermodynamic   properties   may   be   derived   from   the   equations   of   state   and   other 
fundamental thermodynamic equations.

The mechanical or microscopic state of a system is defined by the atomic positions, q, and 
momenta,  p; these can also be considered as coordinates in a multidimensional space 
called phase space. For a system of N particles, this space has 6N dimensions. A single 
point in phase space, denoted by  Γ , describes the state of the system. An  ensemble  is a 
collection   of   points   in   phase   space   satisfying   the   conditions   of   a   particular 
thermodynamic state. A molecular dynamics simulations generates a sequence of points 
in phase space as a function of time; these points belong to the same ensemble, and they 
correspond to the different conformations of the system and their respective momenta. 
Several different ensembles are described below.

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.

• Microcanonical ensemble (NVE) : The thermodynamic state 
characterized by a fixed number of atoms, N, a fixed volume, V, and 
a fixed energy, E. This corresponds to an isolated system.
• Canonical Ensemble (NVT): This is a collection of all systems 
whose thermodynamic state is characterized by a fixed number of 
atoms, N, a fixed volume, V, and a fixed temperature, T.
• Isobaric­Isothermal   Ensemble   (NPT):   This   ensemble   is 
characterized by a fixed number of atoms, N, a fixed pressure, P, 
and a fixed temperature, T.

• Grand canonical Ensemble (µ VT): The thermodynamic state 
for this ensemble is characterized by a fixed chemical potential, µ , 
a fixed volume, V, and a fixed temperature, T.
 CALCULATING AVERAGES FROM A MOLECULAR DYNAMICS SIMULATION

An experiment is usually made on a macroscopic sample that contains an extremely 
large number of atoms or molecules sampling an enormous number of conformations. In 
statistical mechanics, averages corresponding to experimental observables are defined in 
terms   of   ensemble   averages;   one   justification   for   this   is   that   there   has   been   good 
agreement with experiment. An ensemble average is average taken over a large number 
of replicas of the system considered simultaneously.

In statistical mechanics, average values are defined as ensemble averages.

The ensemble average is given by

where

is the observable of interest and it is expressed as a function of the momenta, p, and the 
positions, r, of the system. The integration is over all possible variables of r and p.

The probability density of the ensemble is given by

where H is the Hamiltonian, T is the temperature, kB is Boltzmann’s constant and Q is 
the partition function

This integral is generally  extremely  difficult to calculate because one must calculate all 

possible   states   of   the   system.   In   a   molecular   dynamics   simulation,   the   points   in   the 
ensemble are calculated sequentially in time, so to calculate an ensemble average, the 
molecular dynamics simulations must pass through all possible states corresponding to 
the particular thermodynamic constraints.

Another way, as done in an MD simulation, is to determine a time average of A, which 
is expressed as

where  τ   is the simulation time, M is the number of time steps in the simulation and 
A(pN,rN) is the instantaneous value of A.

The dilemma appears to be that one can calculate time averages by molecular dynamics 
simulation,   but   the   experimental   observables   are   assumed   to   be   ensemble   averages. 
Resolving this leads us to one of the most fundamental axioms of statistical mechanics, 
the ergodic hypothesis, which states that the time average equals the ensemble average.

The Ergodic hypothesis states
 Ensemble average = Time average

The basic idea is that if one allows the system to evolve in time indefinitely, that system 
will   eventually   pass   through   all   possible   states.   One   goal,   therefore,   of   a   molecular 
dynamics simulation is to generate enough representative conformations such that this 
equality is satisfied. If this is the case, experimentally relevant information concerning 
structural,   dynamic   and   thermodynamic   properties   may   then   be   calculated   using   a 
feasible amount of computer resources. Because the simulations are of fixed duration, 
one must be certain to sample a sufficient amount of phase space.

Some examples of time averages:

AVERAGE POTENTIAL ENERGY

where M is the number of configurations in the molecular dynamics trajectory and Vi is 
the potential energy of each configuration.

AVERAGE KINETIC ENERGY

where M is the number of configurations in the simulation, N is the number of atoms in 
the system, mi is the mass of the particle i and vi is the velocity of particle i.

A   molecular   dynamics   simulation   must   be   sufficiently   long   so   that   enough 

representative conformations have been sampled.

4. CLASSICAL MECHANICS

The molecular dynamics simulation method is based on Newton’s 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.   Molecular   dynamics   simulations   can   be   time   consuming   and   computationally 
expensive. However, computers are getting faster and cheaper. Simulations of solvated 
proteins are calculated up to the nanosecond time scale, however, simulations into the 
millisecond regime have been reported.

Newton’s 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,

Combining these two equations yields

where  V  is the potential energy of the system.  Newton’s  equation of motion can then 

relate the derivative of the potential energy to the changes in position as a function of 
time.

NEWTON’S 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,

Therefore, to calculate a trajectory, one only needs the initial positions of the atoms, an 
initial distribution of velocities and the acceleration, which is determined by the gradient 
of   the   potential   energy   function.   The   equations   of   motion   are   deterministic,   e.g.,   the 
positions and the velocities at time zero determine the positions and velocities at all other 
times, t. The initial positions can be obtained from experimental structures, such as the x­
ray   crystal   structure   of   the   protein   or   the   solution   structure   determined   by   NMR 
spectroscopy.

The initial distribution of velocities are usually determined from a random distribution 
with the magnitudes conforming to the required temperature and corrected so there is 
no overall momentum, i.e.,

The velocities,  vi,  are often chosen randomly from a Maxwell­Boltzmann or Gaussian 

distribution at a given temperature, which gives the probability that an atom i has a 
velocity vx in the x direction at a temperature T.

The temperature can be calculated from the velocities using the relation

where N is the number of atoms in the system.

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. We list several here.

•  Verlet algorithm  
•  Leap­frog algorithm  
•  Velocity Verlet  
•  Beeman’s 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 one can write
 Summing these two equations, one obtains

The Verlet algorithm uses positions and accelerations at time  t  and the positions from 

time t­δ t to calculate new positions at time t+δ t. The Verlet algorithm uses no explicit 
velocities. The advantages of the Verlet algorithm are, i) it is straightforward, and ii) the 
storage requirements are modest . The disadvantage is that the algorithm is of moderate 
precision.

THE LEAP­FROG ALGORITHM

In this algorithm, the velocities are first calculated at time  t+1/2δ t; these are used to 

calculate the positions, r, at time t+δ t. 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:

THE VELOCITY VERLET ALGORITHM

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

BEEMAN’S 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.

Use
of Molecular Dynamics Sim
ulation
Kinetics and irreversible processes
•chemical reaction kinetics (with QM)
• conformational changes, allosteric
mechanisms
• Protein folding
Equilibrium ensemble sampling
•Flexibility
• thermodynamics (free energy
changes, binding)
Modeling tool
• structure prediction / modeling
• solvent effects
• NMR/crystallography (refinement)
• Electron microscopy (flexible fitting)

Why
use molecular dynamics?
• MD is a sampling
method. But there are other sampling
methods like MonteCarlo (MC). So why u
se MD?
• MD gives you DYNAMICS. Other
methods can give you the ensemble
(smeared picture), but MD gives you a
movie.
• Dynamics are important because
Biological systems are
compartmentalized and are FAR FROM
EQUILIBRIUM.
• From a small molecule’s standpoint, it
doesn’t matter what the list of potential
structures of a protein are. Instead the
molecule cares about the protein’s
structures over the time it can diffusively
sample (about a nsec). And can the
molecule influence the dynamics during
its contact time?
• Consider highway traffic at rush hour,
midday and at 2 in the morning. The
average (ensemble) picture of the two
doesn’t help the poor frog trying to get
across the highway.

Atomic
Detail Computer Simulation
Model System
Molecular Mechanics Potential

Energy Surface →
Exploration by Simulation..
© Jeremy Smith

Bonded
Interactions: Stretching
Estr represents the energy required to stretch or
compress a covalent bond:
A bond can be thought
of as a spring having its own equilibrium length, ro, and
the energy required to stretch or compress it can be
approximated by the Hookean potential for an ideal
spring:
Estr = ½ ks,ij ( rij - ro )2

Bonded
Interactions: Bending
Ebend is the energy required to bend a bond from its
equilibrium angle, θ o:
Again this system can
be modeled by a spring, and the energy
is given by the Hookean potential with
respect to angle:

Ebend = ½ kb,ijk (θ ijk

-θ o
)2

Bonded
Interactions: Improper Torsio
n
Eimproper is the energy required to deform a planar group
of atoms from its equilibrium angle, ω o, usually equal
to zero:
Again this system can be modeled by a spring, and
the energy is given by the Hookean potential with
respect to planar angle:

Eimproper = ½ ko,ijkl (ω ijkl

-ω o
)2
© Thomas W. Shattuck

ω
i
j
l
k

Bonded Interactions: Torsion

Etor is the energy of torsion needed to rotate about
bonds:

© Thomas W. Shattuck

Torsional interactions are modeled by the potential:

= ½ ktor,1 (1 - cos φ ) +
Etor ½ ktor,2 (1 - cos 2
φ ) + ½ ktor,3 ( 1 - cos 3 φ )
asymmetry (butane) 2-fold groups e.g. COO- standard tetrahedral
torsions
Non-Bonded
Interactions: van der Waals
EvdW is the steric exclusion and long-range attraction
energy (QM origins):
© Thomas W. Shattuck

Two frequently used formulas:

E
E

Non-Bonded
Interactions: Coulomb
Eqq is the Coulomb potential function for electrostatic
interactions of charges:
© Thomas W. Shattuck
Formula:

The Qi and Qj are the partial atomic charges for atoms

i and j separated by a distance rij. ε is the relative
dielectric constant. For gas phase calculations ε is
normally set to 1. Larger values of ε are used to
approximate the dielectric effect of intervening solute
(ε ∼ 60-80) or solvent atoms in solution. k is a units
conversion constant; for kcal/mol, k=2086.4.

Newton’s Law
Newton’s Law:
Esteric energy = Estr + Ebend + Eimproper + Etor +
EvdW + Eqq

Verlet’s
Numeric Integration Method
Taylor expansion:
Verlet’s Method

Timescale Limitations
• Protein Folding
- milliseconds/seconds (10-3-1s)
• Ligand Binding - micro/milliseconds (10-
6
-10-3 s)
• Enzyme catalysis - micro/milliseconds
(10-6-10-3 s)
• Conformational transitions -
pico/nanoseconds (10-12-10-9 s)
• Collective vibrations -
1 picosecond (10-12 s)
• Bond vibrations -
1 femtosecond (10-15 s)
Timescale Limitations
Molecular dynamics:
Integration timestep
- 1 fs, set by fastest varying force.
Accessible timescale:
about 10 nanoseconds.

Cutting Corners
SHAKE, Schlick 12.5
MTS, Schlick 13.3
PME, Schlick 9.4
Input
files for MD simulation
• A starting structure (.pdb)
• A description of structural connections
and atom types (.psf)
• A force field (.par) for the atom types
(charmm, gromacs, amber, etc)
• An input script for the MD program
(.conf)

Input Files: PDB

atomic structures

Input Files: PDB

We will use
ubiquitin (1UBQ) as an example. The
pdb structure is available in the protein data
bank.
First, take a look at the file.
Then view it using vmd.

Input Files: Topology Files

blueprints for building a PSF file

Input Files: Topology Files

The topology
file represents residues in internal coordinates
Input Files: Topology Files
Take a look
at the charmm/xplor topology file top_all27_prot_lipi
d.inp

Input Files: PSF

Use information in
topology file to “fill in the gaps”
of the pdb structure:
• Patch residues
• Add hydrogens
• Add waters

NAMD/VMD uses the

utility psfgen to construct the psf file.
Input Files: PSF

Input Files: PSF

Look at the
Tcl script, ubq.pgn, that uses psfgen
to render the psf file.

Input Files: Parameter Files

defining the MM energy terms

Input Files: Parameter Files

defining the MM energy terms
Take a look
at the charmm force field par_all27_prot_lipid.inp

Production Run Protocol

Different protocols:
• One can do constrained dynamics
at the final temp
Or
• Do free dynamics with a temp ramp-up.

Input Files: MD run script

defining the MM energy terms
NAMD input script ubq_wb_eq.conf
 Output is a
trajectory (mcd) in binary format. Depending
on input script, mcd may contain trajectory
coordinates and trajectory velocities.
Can use vmd to visualize the trajectory.

Data reduction and analysis

MD runs, by virtue
of temperature coupling are stochastic.
• One can calculate
average trajectories by summing over mu
ltiple
runs to get an AVERAGE TRAJECTORY
. This gives information on non-
equilibrium systems.

• More commonly, one

calculates average properties within a sin
gle
run. IFF the MD run has sampled the
entire configurational phase space ( is
ergotic), then the time average = ensemb
le
average. One recovers an ENSEMBLE
AVERAGE.
Ensemble properties of interest include: t
hermodynamic
state functions: free energy (partition fun
ction), entropy, enthalpy

Data reduction and analysis

Averaging is done by
constructing a correlation matrix, where
• Off-diagonal terms
give correlations between atoms.

And
• Diagonal elements
give an average property of an atom.
(ex: the RMSD of a residue). RMSD
from MD can be compared to B-factors
from X-ray chrystallography, H/D protecti
on
factors from NMR data, and order param
eters from NMR, EPR, or fluorescence.

RMSD

MD - energies
energies: kinetic and potential

MD - sampling a local basin

exploring conformations

Biased
MD - jumping barriers
exploring conformations

Biased MD
exploring conformations
MD simulations are
generally bad at sampling phase space.
To cover configurational
phase space, one needs to be able
to do two things well: explore canyons
and jump over energy barriers. Biased
MD algorithms have been devised to overco
me these deficiencies.
• Explore canyons
- accelerated collective motions (ACM) T4
lysozyme example.
http://cmm.info.nih.gov/intro_simulation

MOLECULAR DYNAMICS
From Wikipedia, the free encyclopedia

Jump to: navigation, search

Molecular dynamics (MD) is a form of computer simulation in which atoms and

molecules are allowed to interact for a period of time by approximations of known physics,
giving a view of the motion of the particles. Molecular dynamics simulation is frequently
used in the study of proteins and biomolecules, as well as in materials science. It is
tempting, though not entirely accurate, to describe the technique as a "virtual microscope"
with high temporal and spatial resolution. Whereas it is possible to take "still snapshots" of
crystal structures and probe features of the motion of molecules through NMR, no current
experimental technique allows access to all the time scales of motion with atomic
resolution. Richard Feynman once said that "If we were to name the most powerful
assumption of all, which leads one on and on in an attempt to understand life, it is that all
things are made of atoms, and that everything that living things do can be understood in
terms of the jigglings and wigglings of atoms." Molecular dynamics lets scientists peer into
the motion of individual atoms in a way which is not possible in laboratory experiments.

Molecular dynamics 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[1][2] and allowing insight into molecular motion on an atomic scale. However, long
MD simulations are mathematically ill-conditioned, generating cumulative errors in
numerical integration that can be minimized with proper selection of algorithms and
parameters, but not eliminated entirely. Furthermore, current potential energy functions
(also called force-fields) are, in many cases, not sufficiently accurate to reproduce the
dynamics of molecular systems, so the much more computationally demanding Ab Initio
Molecular Dynamics method must be used. Nevertheless, molecular dynamics techniques
allow detailed time and space resolution into representative behavior in phase space for
carefully selected systems.

Before it became possible to simulate molecular dynamics with computers, some

undertook the hard work of trying it with physical models such as macroscopic spheres.
The idea was to arrange them to replicate the properties of a liquid. J.D. Bernal said, in
1962: "... I took a number of rubber balls and stuck them together with rods of a selection
of different lengths ranging from 2.75 to 4 inches. I tried to do this in the first place as
casually as possible, working in my own office, being interrupted every five minutes or so
and not remembering what I had done before the interruption."[3] Fortunately, now
computers keep track of bonds during a simulation.

Because molecular systems generally consist of a vast number of particles, it is in general

impossible to find the properties of such complex systems analytically. When the number
of particles interacting is higher than two, the result is chaotic motion (see n-body
problem). MD simulation circumvents the analytical intractability by using numerical
methods. It represents an interface between laboratory experiments and theory, and can be
understood as a "virtual experiment". MD probes the relationship between molecular
structure, movement and function. Molecular dynamics is a multidisciplinary method. Its
laws and theories stem from mathematics, physics, and chemistry, and it employs
algorithms from computer science and information theory. It was originally conceived
within theoretical physics in the late 1950s[4] and early 1960s [5], but is applied today mostly
in materials science and the modeling of biomolecules.
 Example of a molecular dynamics simulation in a simple system: deposition of a single Cu
atom on a Cu (001) surface. Each circle illustrates the position of a single atom; note that the
actual atomic interactions used in current simulations are more complex than those of 2-
dimensional hard spheres.

Highly simplified description of the molecular dynamics simulation algorithm. The

simulation proceeds iteratively by alternatively calculating forces and solving the equations of
motion based on the accelerations obtained from the new forces. In practise, almost all MD
codes use much more complicated versions of the algorithm, including two steps (predictor
and corrector) in solving the equations of motion and many additional steps for e.g.
temperature and pressure control, analysis and output.
CONTENTS
[hide]

• 1 Areas of Application
• 2 Design Constraints
o 2.1 Microcanonical ensemble (NVE)
o 2.2 Canonical ensemble (NVT)
o 2.3 Isothermal-Isobaric (NPT) ensemble
o 2.4 Generalized ensembles
• 3 Potentials in MD simulations
o 3.1 Empirical potentials
o 3.2 Pair potentials vs. many-body potentials
o 3.3 Semi-empirical potentials
o 3.4 Polarizable potentials
o 3.5 Ab-initio methods
o 3.6 Hybrid QM/MM
o 3.7 Coarse-graining and reduced representations
• 4 Examples of applications
• 5 Molecular dynamics algorithms
o 5.1 Integrators
o 5.2 Short-range interaction algorithms
o 5.3 Long-range interaction algorithms
o 5.4 Parallelization strategies
• 6 Major software for MD simulations
• 7 Related software
• 8 Specialized hardware for MD simulations
• 9 See also
• 10 References
o 10.1 General references

• 11 External links
[EDIT ] AREAS OF APPLICATION

There is a significant difference between the focus and methods used by chemists and
physicists, and this is reflected in differences in the jargon used by the different fields. In
chemistry and biophysics, the interaction between the particles is either described by a
"force field" (classical MD), a quantum chemical model, or a mix between the two. These
terms are not used in physics, where the interactions are usually described by the name of
the theory or approximation being used and called the potential energy, or just the
"potential".

Beginning in theoretical physics, the method of MD gained popularity in materials science

and since the 1970s also in biochemistry and biophysics. In chemistry, MD serves as an
important tool in protein structure determination and refinement using experimental tools
such as X-ray crystallography and NMR. It has also been applied with limited success as a
method of refining protein structure predictions. In physics, MD is used to examine the
dynamics of atomic-level phenomena that cannot be observed directly, such as thin film
growth and ion-subplantation. It is also used to examine the physical properties of
nanotechnological devices that have not or cannot yet be created.

In applied mathematics and theoretical physics, molecular dynamics is a part of the

research realm of dynamical systems, ergodic theory and statistical mechanics in general.
The concepts of energy conservation and molecular entropy come from thermodynamics.
Some techniques to calculate conformational entropy such as principal components
analysis come from information theory. Mathematical techniques such as the transfer
operator become applicable when MD is seen as a Markov chain. Also, there is a large
community of mathematicians working on volume preserving, symplectic integrators for
more computationally efficient MD simulations.

MD can also be seen as a special case of the discrete element method (DEM) in which the
particles have spherical shape (e.g. with the size of their van der Waals radii.) Some
authors in the DEM community employ the term MD rather loosely, even when their
simulations do not model actual molecules.

[EDIT ] DESIGN CONSTRAINTS

Design of a molecular dynamics simulation should account for the available

computational power. Simulation size (n=number of particles), timestep and total time
duration must be selected so that the calculation can finish within a reasonable time period.
However, the simulations should be long enough to be relevant to the time scales of the
natural processes being studied. To make statistically valid conclusions from the
simulations, the time span simulated should match the kinetics of the natural process.
Otherwise, it is analogous to making conclusions about how a human walks from less than
one footstep. Most scientific publications about the dynamics of proteins and DNA use data
from simulations spanning nanoseconds (1E-9 s) to microseconds (1E-6 s). To obtain these
simulations, several CPU-days to CPU-years are needed. Parallel algorithms allow the load
to be distributed among CPUs; an example is the spatial or force decomposition algorithm
[1].

During a classical MD simulation, the most CPU intensive task is the evaluation of the
potential (force field) as a function of the particles' internal coordinates. Within that energy
evaluation, the most expensive one is the non-bonded or non-covalent part. In Big O
notation, common molecular dynamics simulations scale by O(n2) if all pair-wise
electrostatic and van der Waals interactions must be accounted for explicitly. This
computational cost can be reduced by employing electrostatics methods such as Particle
Mesh Ewald ( O(nlog(n)) ), P3M or good spherical cutoff techniques ( O(n) ).

Another factor that impacts total CPU time required by a simulation is the size of the
integration timestep. This is the time length between evaluations of the potential. The
timestep must be chosen small enough to avoid discretization errors (i.e. smaller than the
fastest vibrational frequency in the system). Typical timesteps for classical MD are in the
order of 1 femtosecond (1E-15 s). This value may be extended by using algorithms such as
SHAKE, which fix the vibrations of the fastest atoms (e.g. hydrogens) into place. Multiple
time scale methods have also been developed, which allow for extended times between
updates of slower long-range forces.[6][7][8]

For simulating molecules in a solvent, a choice should be made between explicit solvent
and implicit solvent. Explicit solvent particles (such as the TIP3P, SPC/E and SPC-f water
models) must be calculated expensively by the force field, while implicit solvents use a
mean-field approach. Using an explicit solvent is computationally expensive, requiring
inclusion of roughly ten times more particles in the simulation. But the granularity and
viscosity of explicit solvent is essential to reproduce certain properties of the solute
molecules. This is especially important to reproduce kinetics.

In all kinds of molecular dynamics simulations, the simulation box size must be large
enough to avoid boundary condition artifacts. Boundary conditions are often treated by
choosing fixed values at the edges (which may cause artifacts), or by employing periodic
boundary conditions in which one side of the simulation loops back to the opposite side,
mimicking a bulk phase.

[EDIT ] MICROCANONICAL ENSEMBLE (NVE)

In the microcanonical, or NVE ensemble, the system is isolated from changes in moles
(N), volume (V) and energy (E). It corresponds to an adiabatic process with no heat
exchange. A microcanonical molecular dynamics trajectory may be seen as an exchange of
potential and kinetic energy, with total energy being conserved. For a system of N particles
with coordinates X and velocities V, the following pair of first order differential equations
may be written in Newton's notation as

The potential energy function U(X) of the system is a function of the particle coordinates
X. It is referred to simply as the "potential" in Physics, or the "force field" in Chemistry.
The first equation comes from Newton's laws; the force F acting on each particle in the
system can be calculated as the negative gradient of U(X).

For every timestep, each particle's position X and velocity V may be integrated with a
symplectic method such as Verlet. The time evolution of X and V is called a trajectory.
Given the initial positions (e.g. from theoretical knowledge) and velocities (e.g.
randomized Gaussian), we can calculate all future (or past) positions and velocities.

One frequent source of confusion is the meaning of temperature in MD. Commonly we

have experience with macroscopic temperatures, which involve a huge number of particles.
But temperature is a statistical quantity. If there is a large enough number of atoms,
statistical temperature can be estimated from the instantaneous temperature, which is
found by equating the kinetic energy of the system to nkBT/2 where n is the number of
degrees of freedom of the system.

A temperature-related phenomenon arises due to the small number of atoms that are used
in MD simulations. For example, consider simulating the growth of a copper film starting
with a substrate containing 500 atoms and a deposition energy of 100 eV. In the real world,
the 100 eV from the deposited atom would rapidly be transported through and shared
among a large number of atoms (1010 or more) with no big change in temperature. When
there are only 500 atoms, however, the substrate is almost immediately vaporized by the
deposition. Something similar happens in biophysical simulations. The temperature of the
system in NVE is naturally raised when macromolecules such as proteins undergo
exothermic conformational changes and binding.

[EDIT ] CANONICAL ENSEMBLE (NVT)

In the canonical ensemble, moles (N), volume (V) and temperature (T) are conserved. It is
also sometimes called constant temperature molecular dynamics (CTMD). In NVT, the
energy of endothermic and exothermic processes is exchanged with a thermostat.

A variety of thermostat methods is available to add and remove energy from the
boundaries of an MD system in a more or less realistic way, approximating the canonical
ensemble. Popular techniques to control temperature include velocity rescaling, the Nosé-
Hoover thermostat, Nosé-Hoover chains, the Berendsen thermostat and Langevin
dynamics. Note that the Berendsen thermostat might introduce the flying ice cube effect,
which leads to unphysical translations and rotations of the simulated system.

It is not trivial to obtain a canonical distribution of conformations and velocities using

these algorithms. How this depends on system size, thermostat choice, thermostat
parameters, time step and integrator is the subject of many articles in the field.

[EDIT ] ISOTHERMAL-ISOBARIC (NPT) ENSEMBLE

In the isothermal-isobaric ensemble, moles (N), pressure (P) and temperature (T) are
conserved. In addition to a thermostat, a barostat is needed. It corresponds most closely to
laboratory conditions with a flask open to ambient temperature and pressure.

In the simulation of biological membranes, isotropic pressure control is not appropriate.

For lipid bilayers, pressure control occurs under constant membrane area (NPAT) or
constant surface tension "gamma" (NPγT).

[EDIT ] GENERALIZED ENSEMBLES

The replica exchange method is a generalized ensemble. It was originally created to deal
with the slow dynamics of disordered spin systems. It is also called parallel tempering. The
replica exchange MD (REMD) formulation [9] tries to overcome the multiple-minima
problem by exchanging the temperature of non-interacting replicas of the system running at
several temperatures.

[EDIT ] POTENTIALS IN MD SIMULATIONS

Main articles: Force field and Force field implementation

A molecular dynamics simulation requires the definition of a potential function, or a

description of the terms by which the particles in the simulation will interact. In chemistry
and biology this is usually referred to as a force field. Potentials may be defined at many
levels of physical accuracy; those most commonly used in chemistry are based on
molecular mechanics and embody a classical treatment of particle-particle interactions that
can reproduce structural and conformational changes but usually cannot reproduce
chemical reactions.

The reduction from a fully quantum description to a classical potential entails two main
approximations. The first one is the Born-Oppenheimer approximation, which states that
the dynamics of electrons is so fast that they can be considered to react instantaneously to
the motion of their nuclei. As a consequence, they may be treated separately. The second
one treats the nuclei, which are much heavier than electrons, as point particles that follow
classical Newtonian dynamics. In classical molecular dynamics the effect of the electrons is
approximated as a single potential energy surface, usually representing the ground state.

When finer levels of detail are required, potentials based on quantum mechanics are used;
some techniques attempt to create hybrid classical/quantum potentials where the bulk of the
system is treated classically but a small region is treated as a quantum system, usually
undergoing a chemical transformation.

[EDIT ] EMPIRICAL POTENTIALS

Empirical potentials used in chemistry are frequently called force fields, while those used
in materials physics are called just empirical or analytical potentials.

Most force fields in chemistry are empirical and consist of a summation of bonded forces
associated with chemical bonds, bond angles, and bond dihedrals, and non-bonded forces
associated with van der Waals forces and electrostatic charge. Empirical potentials
represent quantum-mechanical effects in a limited way through ad-hoc functional
approximations. These potentials contain free parameters such as atomic charge, van der
Waals parameters reflecting estimates of atomic radius, and equilibrium bond length, angle,
and dihedral; these are obtained by fitting against detailed electronic calculations (quantum
chemical simulations) or experimental physical properties such as elastic constants, lattice
parameters and spectroscopic measurements.

Because of the non-local nature of non-bonded interactions, they involve at least weak
interactions between all particles in the system. Its calculation is normally the bottleneck in
the speed of MD simulations. To lower the computational cost, force fields employ
numerical approximations such as shifted cutoff radii, reaction field algorithms, particle
mesh Ewald summation, or the newer Particle-Particle Particle Mesh (P3M).

Chemistry force fields commonly employ preset bonding arrangements (an exception
being ab-initio dynamics), and thus are unable to model the process of chemical bond
breaking and reactions explicitly. On the other hand, many of the potentials used in
physics, such as those based on the bond order formalism can describe several different
coordinations of a system and bond breaking. Examples of such potentials include the
Brenner potential[10] for hydrocarbons and its further developments for the C-Si-H and C-O-
H systems. The ReaxFF potential[11] can be considered a fully reactive hybrid between bond
order potentials and chemistry force fields.

[EDIT ] PAIR POTENTIALS VS. MANY-BODY POTENTIALS

The potential functions representing the non-bonded energy are formulated as a sum over
interactions between the particles of the system. The simplest choice, employed in many
popular force fields, is the "pair potential", in which the total potential energy can be
calculated from the sum of energy contributions between pairs of atoms. An example of
such a pair potential is the non-bonded Lennard-Jones potential (also known as the 6-12
potential), used for calculating van der Waals forces.

Another example is the Born (ionic) model of the ionic lattice. The first term in the next
equation is Coulomb's law for a pair of ions, the second term is the short-range repulsion
explained by Pauli's exclusion principle and the final term is the dispersion interaction
term. Usually, a simulation only includes the dipolar term, although sometimes the
quadrupolar term is included as well.

In many-body potentials, the potential energy includes the effects of three or more
particles interacting with each other. In simulations with pairwise potentials, global
interactions in the system also exist, but they occur only through pairwise terms. In many-
body potentials, the potential energy cannot be found by a sum over pairs of atoms, as these
interactions are calculated explicitly as a combination of higher-order terms. In the
statistical view, the dependency between the variables cannot in general be expressed using
only pairwise products of the degrees of freedom. For example, the Tersoff potential[12],
which was originally used to simulate carbon, silicon and germanium and has since been
used for a wide range of other materials, involves a sum over groups of three atoms, with
the angles between the atoms being an important factor in the potential. Other examples are
the embedded-atom method (EAM)[13] and the Tight-Binding Second Moment
Approximation (TBSMA) potentials[14], where the electron density of states in the region of
an atom is calculated from a sum of contributions from surrounding atoms, and the
potential energy contribution is then a function of this sum.

[EDIT ] SEMI-EMPIRICAL POTENTIALS

Semi-empirical potentials make use of the matrix representation from quantum mechanics.
However, the values of the matrix elements are found through empirical formulae that
estimate the degree of overlap of specific atomic orbitals. The matrix is then diagonalized
to determine the occupancy of the different atomic orbitals, and empirical formulae are
used once again to determine the energy contributions of the orbitals.

There are a wide variety of semi-empirical potentials, known as tight-binding potentials,

which vary according to the atoms being modeled.

[EDIT ] POLARIZABLE POTENTIALS

Main article: Force field

Most classical force fields implicitly include the effect of polarizability, e.g. by scaling up
the partial charges obtained from quantum chemical calculations. These partial charges are
stationary with respect to the mass of the atom. But molecular dynamics simulations can
explicitly model polarizability with the introduction of induced dipoles through different
methods, such as Drude particles or fluctuating charges. This allows for a dynamic
redistribution of charge between atoms which responds to the local chemical environment.

For many years, polarizable MD simulations have been touted as the next generation. For
homogenous liquids such as water, increased accuracy has been achieved through the
inclusion of polarizability.[15] Some promising results have also been achieved for proteins.
[16]
However, it is still uncertain how to best approximate polarizability in a simulation.
[citation needed]

[EDIT ] AB-INITIO METHODS

In classical molecular dynamics, a single potential energy surface (usually the ground
state) is represented in the force field. This is a consequence of the Born-Oppenheimer
approximation. In excited states, chemical reactions or a more accurate representation is
needed, electronic behavior can be obtained from first principles by using a quantum
mechanical method, such as Density Functional Theory. This is known as Ab Initio
Molecular Dynamics (AIMD). Due to the cost of treating the electronic degrees of
freedom, the computational cost of this simulations is much higher than classical molecular
dynamics. This implies that AIMD is limited to smaller systems and shorter periods of
time.

Ab-initio quantum-mechanical methods may be used to calculate the potential energy of a

system on the fly, as needed for conformations in a trajectory. This calculation is usually
made in the close neighborhood of the reaction coordinate. Although various
approximations may be used, these are based on theoretical considerations, not on
empirical fitting. Ab-Initio calculations produce a vast amount of information that is not
available from empirical methods, such as density of electronic states or other electronic
properties. A significant advantage of using ab-initio methods is the ability to study
reactions that involve breaking or formation of covalent bonds, which correspond to
multiple electronic states.

A popular software for ab-initio molecular dynamics is the Car-Parrinello Molecular

Dynamics (CPMD) package based on the density functional theory.

[EDIT ] HYBRID QM/MM

QM (quantum-mechanical) methods are very powerful. However, they are

computationally expensive, while the MM (classical or molecular mechanics) methods are
fast but suffer from several limitations (require extensive parameterization; energy
estimates obtained are not very accurate; cannot be used to simulate reactions where
covalent bonds are broken/formed; and are limited in their abilities for providing accurate
details regarding the chemical environment). A new class of method has emerged that
combines the good points of QM (accuracy) and MM (speed) calculations. These methods
are known as mixed or hybrid quantum-mechanical and molecular mechanics methods
(hybrid QM/MM). The methodology for such techniques was introduced by Warshel and
coworkers. In the recent years have been pioneered by several groups including: Arieh
Warshel (University of Southern California), Weitao Yang (Duke University), Sharon
Hammes-Schiffer (The Pennsylvania State University), Donald Truhlar and Jiali Gao
(University of Minnesota) and Kenneth Merz (University of Florida).

The most important advantage of hybrid QM/MM methods is the speed. The cost of doing
classical molecular dynamics (MM) in the most straightforward case scales O(n2), where N
is the number of atoms in the system. This is mainly due to electrostatic interactions term
(every particle interacts with every other particle). However, use of cutoff radius, periodic
pair-list updates and more recently the variations of the particle-mesh Ewald's (PME)
method has reduced this between O(N) to O(n2). In other words, if a system with twice as
many atoms is simulated then it would take between two to four times as much computing
power. On the other hand the simplest ab-initio calculations typically scale O(n3) or worse
(Restricted Hartree-Fock calculations have been suggested to scale ~O(n2.7)). To overcome
the limitation, a small part of the system is treated quantum-mechanically (typically active-
site of an enzyme) and the remaining system is treated classically.

In more sophisticated implementations, QM/MM methods exist to treat both light nuclei
susceptible to quantum effects (such as hydrogens) and electronic states. This allows
generation of hydrogen wave-functions (similar to electronic wave-functions). This
methodology has been useful in investigating phenomena such as hydrogen tunneling. One
example where QM/MM methods have provided new discoveries is the calculation of
hydride transfer in the enzyme liver alcohol dehydrogenase. In this case, tunneling is
important for the hydrogen, as it determines the reaction rate.[17]
[EDIT ] COARSE-GRAINING AND REDUCED REPRESENTATIONS

At the other end of the detail scale are coarse-grained and lattice models. Instead of
explicitly representing every atom of the system, one uses "pseudo-atoms" to represent
groups of atoms. MD simulations on very large systems may require such large computer
resources that they cannot easily be studied by traditional all-atom methods. Similarly,
simulations of processes on long timescales (beyond about 1 microsecond) are
prohibitively expensive, because they require so many timesteps. In these cases, one can
sometimes tackle the problem by using reduced representations, which are also called
coarse-grained models.

Examples for coarse graining (CG) methods are discontinuous molecular dynamics (CG-
DMD)[18][19] and Go-models[20]. Coarse-graining is done sometimes taking larger pseudo-
atoms. Such united atom approximations have been used in MD simulations of biological
membranes. The aliphatic tails of lipids are represented by a few pseudo-atoms by
gathering 2 to 4 methylene groups into each pseudo-atom.

The parameterization of these very coarse-grained models must be done empirically, by

matching the behavior of the model to appropriate experimental data or all-atom
simulations. Ideally, these parameters should account for both enthalpic and entropic
contributions to free energy in an implicit way. When coarse-graining is done at higher
levels, the accuracy of the dynamic description may be less reliable. But very coarse-
grained models have been used successfully to examine a wide range of questions in
structural biology.

Examples of applications of coarse-graining in biophysics:

• protein folding studies are often carried out using a single (or a few) pseudo-atoms per
amino acid;
• DNA supercoiling has been investigated using 1-3 pseudo-atoms per basepair, and at
even lower resolution;
• Packaging of double-helical DNA into bacteriophage has been investigated with models
where one pseudo-atom represents one turn (about 10 basepairs) of the double helix;
• RNA structure in the ribosome and other large systems has been modeled with one
pseudo-atom per nucleotide.

The simplest form of coarse-graining is the "united atom" (sometimes called "extended
atom") and was used in most early MD simulations of proteins, lipids and nucleic acids.
For example, instead of treating all four atoms of a CH3 methyl group explicitly (or all
three atoms of CH2 methylene group), one represents the whole group with a single
pseudo-atom. This pseudo-atom must, of course, be properly parameterized so that its van
der Waals interactions with other groups have the proper distance-dependence. Similar
considerations apply to the bonds, angles, and torsions in which the pseudo-atom
participates. In this kind of united atom representation, one typically eliminates all explicit
hydrogen atoms except those that have the capability to participate in hydrogen bonds
("polar hydrogens"). An example of this is the Charmm 19 force-field.
 The polar hydrogens are usually retained in the model, because proper treatment of
hydrogen bonds requires a reasonably accurate description of the directionality and the
electrostatic interactions between the donor and acceptor groups. A hydroxyl group, for
example, can be both a hydrogen bond donor and a hydrogen bond acceptor, and it would
be impossible to treat this with a single OH pseudo-atom. Note that about half the atoms in
a protein or nucleic acid are nonpolar hydrogens, so the use of united atoms can provide a
substantial savings in computer time.

[EDIT ] EXAMPLES OF APPLICATIONS

Molecular dynamics is used in many fields of science.

• 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.[21]

• 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.[22][23]

The following two biophysical examples are not run-of-the-mill MD simulations. They
illustrate notable efforts to produce simulations of a system of very large size (a complete
virus) and very long simulation times (500 microseconds):

• MD simulation of the complete satellite tobacco mosaic virus (STMV) (2006, Size: 1
million atoms, Simulation time: 50 ns, program: NAMD) This virus is a small, icosahedral
plant virus which worsens the symptoms of infection by Tobacco Mosaic Virus (TMV).
Molecular dynamics simulations were used to probe the mechanisms of viral assembly. The
entire STMV particle consists of 60 identical copies of a single protein that make up the viral
capsid (coating), and a 1063 nucleotide single stranded RNA genome. One key finding is that
the capsid is very unstable when there is no RNA inside. The simulation would take a single
2006 desktop computer around 35 years to complete. It was thus done in many processors in
parallel with continuous communication between them.[24]

• Folding Simulations of the Villin Headpiece in All-Atom Detail (2006, Size: 20,000
atoms; Simulation time: 500 µs = 500,000 ns, Program: folding@home) This simulation was
run in 200,000 CPU's of participating personal computers around the world. These
computers had the folding@home program installed, a large-scale distributed computing
effort coordinated by Vijay Pande at Stanford University. The kinetic properties of the Villin
Headpiece protein were probed by using many independent, short trajectories run by CPU's
without continuous real-time communication. One technique employed was the Pfold value
analysis, which measures the probability of folding before unfolding of a specific starting
conformation. Pfold gives information about transition state structures and an ordering of
conformations along the folding pathway. Each trajectory in a Pfold calculation can be
relatively short, but many independent trajectories are needed.[25]

[EDIT ] MOLECULAR DYNAMICS ALGORITHMS

[EDIT ] INTEGRATORS

• Verlet-Stoermer integration
• Runge-Kutta integration
• Beeman's algorithm
• Gear predictor - corrector
• Constraint algorithms (for constrained systems)
• Symplectic integrator

[EDIT ] SHORT-RANGE INTERACTION ALGORITHMS

• Cell lists
• Verlet list
• Bonded interactions

[EDIT ] LONG-RANGE INTERACTION ALGORITHMS

• Ewald summation
• Particle Mesh Ewald (PME)
• Particle-Particle Particle Mesh P3M
• Reaction Field Method

[EDIT ] PARALLELIZATION STRATEGIES

• Domain decomposition method (Distribution of system data for parallel computing)

• Molecular Dynamics - Parallel Algorithms

[EDIT ] MAJOR SOFTWARE FOR MD SIMULATIONS

Main article: List of software for molecular mechanics modeling

• AutoDock suite of automated docking tools,

• Autodock Vina improved local search algorithm, suite of automated docking tools,
• Abalone (classical, implicit water)
• ABINIT (DFT)
• ACEMD (running on NVIDIA GPUs: heavily optimized with CUDA)
• ADUN (classical, P2P database for simulations)
• AMBER (classical)
• Ascalaph (classical, GPU accelerated)
• CASTEP (DFT)
• CPMD (DFT)
• CP2K (DFT)
• CHARMM (classical, the pioneer in MD simulation, extensive analysis tools)
• COSMOS (classical and hybrid QM/MM, quantum-mechanical atomic charges with
BPT)
• Desmond (classical, parallelization with up to thousands of CPU's)
• Culgi (classical, OPLS-AA, Dreiding, Nerd, and TraPPE-UA force fields)
• DL_POLY (classical)
• ESPResSo (classical, coarse-grained, parallel, extensible)
• Fireball (tight-binding DFT)
• GROMACS (classical)
• GROMOS (classical)
• GULP (classical)
• Hippo (classical)
• HOOMD-Blue (classical, accelerated by NVIDIA GPUs, heavily optimized with
CUDA)
• Kalypso MD simulation of atomic collisions in solids
• LAMMPS (classical, large-scale with spatial-decomposition of simulation domain for
parallelism)
• LPMD Las Palmeras Molecular Dynamics: flexible an modular MD.
• MacroModel (classical)
• MDynaMix (classical, parallel)
• MOLDY (classical, parallel) latest release
• Materials Studio (Forcite MD using COMPASS, Dreiding, Universal, cvff and pcff
forcefields in serial or parallel, QMERA (QM+MD), ONESTEP (DFT), etc.)
• MOSCITO (classical)
• NAMD (classical, parallelization with up to thousands of CPU's)
• nano-Material Simulation Toolkit
• NEWTON-X (ab initio, surface-hopping dynamics)
• ORAC (classical)
• ProtoMol (classical, extensible, includes multigrid electrostatics)
• PWscf (DFT)
• RedMD (coarse-grained simulations package on GNU licence)
• S/PHI/nX (DFT)
• SIESTA (DFT)
• VASP (DFT)
• TINKER (classical)
• YASARA (classical)
• XMD (classical)

[EDIT ] RELATED SOFTWARE

• Avizo - 3d visualization and analysis software.

• BOSS - MC in OPLS
• esra - Lightweight molecular modeling and analysis library
(Java/Jython/Mathematica).
• Molecular Workbench - Interactive molecular simulations on your desktop.
• Packmol Package for building starting configurations for MD in an automated fashion.
• Punto is a freely available visualisation tool for particle simulations.
• PyMol - Molecular Visualization software written in python.
• Sirius - Molecular modeling, analysis and visualization of MD trajectories.
• VMD - MD simulation trajectories can be visualized and analyzed.

[EDIT ] SPECIALIZED HARDWARE FOR MD SIMULATIONS

• Anton - A specialized, massively parallel supercomputer designed to execute MD

simulations.
 • MDGRAPE - A special purpose system built for molecular dynamics simulations,
especially protein structure prediction.