Molecular dynamics
Molecular dynamics (MD) is a computer simulation method for studying the physical movements of atoms and molecules, and is thus a type of Nbody simulation. The atoms and molecules are allowed to interact for a fixed period of time, giving a view of the dynamical evolution of the system. In the most common version, the trajectories of atoms and molecules are determined by numerically solving Newton's equations of motion for a system of interacting particles, where forces between the particles and their potential energies are calculated using interatomic potentials or molecular mechanics force fields. The method was originally developed within the field of theoretical physics in the late 1950s^{[1]}^{[2]} but is applied today mostly in chemical physics, materials science and the modelling of biomolecules.
Because molecular systems typically consist of a vast number of particles, it is impossible to determine the properties of such complex systems analytically; MD simulation circumvents this problem by using numerical methods. However, long MD simulations are mathematically illconditioned, generating cumulative errors in numerical integration that can be minimized with proper selection of algorithms and parameters, but not eliminated entirely.
For systems which obey the ergodic hypothesis, the evolution of a single molecular dynamics simulation may be used to determine macroscopic thermodynamic properties of the system: the time averages of an ergodic system correspond to microcanonical ensemble averages. 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^{[3]}^{[4]} and allowing insight into molecular motion on an atomic scale.
Contents
 History 1
 Areas of application and limitations 2

Design constraints 3
 Microcanonical ensemble (NVE) 3.1
 Canonical ensemble (NVT) 3.2
 Isothermal–isobaric (NPT) ensemble 3.3
 Generalized ensembles 3.4

Potentials in MD simulations 4
 Empirical potentials 4.1
 Pair potentials versus manybody potentials 4.2
 Semiempirical potentials 4.3
 Polarizable potentials 4.4
 Potentials in abinitio methods 4.5
 Hybrid QM/MM 4.6
 Coarsegraining and reduced representations 4.7
 Steered molecular dynamics (SMD) 5
 Examples of applications 6

Molecular dynamics algorithms 7
 Integrators 7.1
 Shortrange interaction algorithms 7.2
 Longrange interaction algorithms 7.3
 Parallelization strategies 7.4
 Specialized hardware for MD simulations 8
 Graphics card as a hardware for MD simulations 9
 See also 10

References 11
 General references 11.1
 External links 12
History
Following the earlier successes of Monte Carlo simulations, the method was developed by Alder and Wainwright in late 50s^{[1]} and Rahman (independently) in the 60s.^{[2]} In 1957, Alder and Wainwright used an IBM 704 computer to simulate perfectly elastic collisions between hard spheres.^{[1]} In 1960, Gibson et al. simulated radiation damage of solid copper by using a BornMayer type of repulsive interaction along with a cohesive surface force.^{[5]} In 1964, Rahman published landmark simulations of liquid argon that utilized a LennardJones potential. Calculations of system properties, such as the coefficient of selfdiffusion, compared well with experimental data.^{[2]}
Even 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."^{[6]}
Areas of application and limitations
Beginning in theoretical physics, the method of MD gained popularity in materials science and since the 1970s also in biochemistry and biophysics. MD is frequently used to refine threedimensional structures of proteins and other macromolecules based on experimental constraints from Xray crystallography or NMR spectroscopy. In physics, MD is used to examine the dynamics of atomiclevel phenomena that cannot be observed directly, such as thin film growth and ionsubplantation. It is also used to examine the physical properties of nanotechnological devices that have not or cannot yet be created. In biophysics and structural biology, the method is frequently applied to study the motions of biological macromolecules such as proteins and nucleic acids, which can be useful for interpreting the results of certain biophysical experiments and for modeling interactions with other molecules, as in ligand docking. In principle MD can be used for ab initio prediction of protein structure by simulating folding of the polypeptide chain from random coil.
The results of MD simulations can be tested through comparison to experiments that measure molecular dynamics, of which a popular method is nuclear magnetic resonance spectroscopy. MDderived structure predictions can be tested through communitywide experiments in protein structure prediction, although the method has historically had limited success in this area. Michael Levitt, who shared the Nobel Prize awarded in part for the application of MD to proteins, wrote in 1999 that CASP participants usually did not use the method due to "a central embarrassment of molecular mechanics, namely that energy minimization or molecular dynamics generally leads to a model that is less like the experimental structure".^{[7]} Improvements in computational resources permitting more and longer MD trajectories to be calculated, combined with modern improvements in the quality of force field parameters, have yielded some improvements in performance of both structure prediction and homology model refinement, without reaching the point of practical utility in these areas; most such work identifies force field parameters as a key area for further development.^{[8]}^{[9]}^{[10]}
Limitations of the method are related not only to the parameter sets used, but also to the underlying molecular mechanics force fields themselves. A single run of an MD simulation optimizes the potential energy, rather than the free energy of the protein, meaning that all entropic contributions to thermodynamic stability of protein structure are neglected. The neglected contributions include the conformational entropy of the polypeptide chain (which is the main factor that destabilizes protein structure) and hydrophobic interactions that are known as main driving force of protein folding.^{[11]} Another important factor are intramolecular hydrogen bonds,^{[12]} which are not explicitly included in modern force fields, but described as Coulomb interactions of atomic point charges. This is a crude approximation because hydrogen bonds have a partially quantum mechanical nature. Furthermore, electrostatic interactions are usually calculated using the dielectric constant of vacuum, although the surrounding aqueous solution has a much higher dielectric constant. Using the macroscopic dielectric constant at short interatomic distances is questionable. Finally, van der Waals interactions in MD are usually described by LennardJones potentials based on the Fritz London theory that is only applicable in vacuum. However, all types of van der Waals forces are ultimately of electrostatic origin and therefore depend on dielectric properties of the environment.^{[13]} The direct measurement of attraction forces between different materials (as Hamaker constant) shows that "the interaction between hydrocarbons across water is about 10% of that across vacuum".^{[13]} The environmentdependence of van der Waals forces is neglected in standard simulations, but can be included by developing polarizable force fields.
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 when only looking at less than one footstep. Most scientific publications about the dynamics of proteins and DNA use data from simulations spanning nanoseconds (10^{−9} s) to microseconds (10^{−6} s). To obtain these simulations, several CPUdays to CPUyears are needed. Parallel algorithms allow the load to be distributed among CPUs; an example is the spatial or force decomposition algorithm.^{[14]}
During a classical MD simulation, the most CPU intensive task is the evaluation of the potential as a function of the particles' internal coordinates. Within that energy evaluation, the most expensive one is the nonbonded or noncovalent part. In Big O notation, common molecular dynamics simulations scale by O(n^2) if all pairwise 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(n \log(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 (10^{−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 longrange forces.^{[15]}^{[16]}^{[17]}
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 SPCf water models) must be calculated expensively by the force field, while implicit solvents use a meanfield 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.
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
 F(X) = \nabla U(X)=M\dot{V}(t)
 V(t) = \dot{X} (t).
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 time step, 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 nk_{B}T/2 where n is the number of degrees of freedom of the system.
A temperaturerelated 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 (10^{10} 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.
Canonical ensemble (NVT)
In the canonical ensemble, amount of substance (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 algorithms is available to add and remove energy from the boundaries of an MD simulation in a more or less realistic way, approximating the canonical ensemble. Popular techniques to control temperature include velocity rescaling, the NoséHoover thermostat, NoséHoover chains, the Berendsen thermostat, the Andersen 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.
Isothermal–isobaric (NPT) ensemble
In the isothermal–isobaric ensemble, amount of substance (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).
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^{[18]} tries to overcome the multipleminima problem by exchanging the temperature of noninteracting replicas of the system running at several temperatures.
Potentials in MD simulations
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 and in materials physics as an interatomic potential. 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 particleparticle 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.
Empirical potentials
Empirical potentials used in chemistry are frequently called force fields, while those used in materials physics are called interatomic 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 nonbonded forces associated with van der Waals forces and electrostatic charge. Empirical potentials represent quantummechanical effects in a limited way through adhoc 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 nonlocal nature of nonbonded 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 ParticleParticle Particle Mesh (P3M).
Chemistry force fields commonly employ preset bonding arrangements (an exception being abinitio 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.^{[19]}^{[20]} Examples of such potentials include the Brenner potential^{[21]} for hydrocarbons and its further developments for the CSiH^{[22]} and COH^{[23]} systems. The ReaxFF potential^{[24]} can be considered a fully reactive hybrid between bond order potentials and chemistry force fields.
Pair potentials versus manybody potentials
The potential functions representing the nonbonded energy are formulated as a sum over interactions between the particles of the system. The simplest choice, employed in many popular force field (physics), 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 nonbonded Lennard–Jones potential (also known as the 6–12 potential), used for calculating van der Waals forces.
 U(r) = 4\varepsilon \left[ \left(\frac{\sigma}{r}\right)^{12}  \left(\frac{\sigma}{r}\right)^{6} \right]
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 shortrange 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.(Usually known as Buckingham potential model)
 U_{ij}(r_{ij}) = \frac {z_i z_j}{4 \pi \epsilon_0} \frac {1}{r_{ij}} + A_l \exp \frac {r_{ij}}{p_l} + C_l r_{ij}^{n_l} + \cdots
In manybody 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 manybody potentials, the potential energy cannot be found by a sum over pairs of atoms, as these interactions are calculated explicitly as a combination of higherorder 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,^{[25]} 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 embeddedatom method (EAM)^{[26]} and the TightBinding Second Moment Approximation (TBSMA) potentials,^{[27]} 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.
Semiempirical potentials
Semiempirical 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 semiempirical potentials, known as tightbinding potentials, which vary according to the atoms being modeled.
Polarizable potentials
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.^{[28]} Some promising results have also been achieved for proteins.^{[29]} However, it is still uncertain how to best approximate polarizability in a simulation.
Potentials in abinitio 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 when 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.
Abinitio quantummechanical 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. Abinitio 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 abinitio methods is the ability to study reactions that involve breaking or formation of covalent bonds, which correspond to multiple electronic states.
Hybrid QM/MM
QM (quantummechanical) 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 quantummechanical and molecular mechanics methods (hybrid QM/MM).^{[30]}
The most important advantage of hybrid QM/MM method is the speed. The cost of doing classical molecular dynamics (MM) in the most straightforward case scales O(n^{2}), 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 pairlist updates and more recently the variations of the particlemesh Ewald's (PME) method has reduced this between O(n) to O(n^{2}). 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 abinitio calculations typically scale O(n^{3}) or worse (Restricted Hartree–Fock calculations have been suggested to scale ~O(n^{2.7})). To overcome the limitation, a small part of the system is treated quantummechanically (typically activesite 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 wavefunctions (similar to electronic wavefunctions). 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.^{[31]}
Coarsegraining and reduced representations
At the other end of the detail scale are coarsegrained and lattice models. Instead of explicitly representing every atom of the system, one uses "pseudoatoms" 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 allatom methods. Similarly, simulations of processes on long timescales (beyond about 1 microsecond) are prohibitively expensive, because they require so many time steps. In these cases, one can sometimes tackle the problem by using reduced representations, which are also called coarsegrained models.
Examples for coarse graining (CG) methods are discontinuous molecular dynamics (CGDMD)^{[32]}^{[33]} and Gomodels.^{[34]} Coarsegraining is done sometimes taking larger pseudoatoms. Such united atom approximations have been used in MD simulations of biological membranes. Implementation of such approach on systems where electrical properties are of interest can be challenging owing to the difficulty of using a proper charge distribution on the pseudoatoms.^{[35]} The aliphatic tails of lipids are represented by a few pseudoatoms by gathering 2 to 4 methylene groups into each pseudoatom.
The parameterization of these very coarsegrained models must be done empirically, by matching the behavior of the model to appropriate experimental data or allatom simulations. Ideally, these parameters should account for both enthalpic and entropic contributions to free energy in an implicit way. When coarsegraining is done at higher levels, the accuracy of the dynamic description may be less reliable. But very coarsegrained models have been used successfully to examine a wide range of questions in structural biology, liquid crystal organization, and polymer glasses.
Examples of applications of coarsegraining:
 protein folding studies are often carried out using a single (or a few) pseudoatoms per amino acid;
 liquid crystal phase transitions have been examined in confined geometries and/or during flow using the GayBerne potential, which describes anisotropic species;
 Polymer glasses during deformation have been studied using simple harmonic or FENE springs to connect spheres described by the LennardJones potential;
 DNA supercoiling has been investigated using 1–3 pseudoatoms per basepair, and at even lower resolution;
 Packaging of doublehelical DNA into bacteriophage has been investigated with models where one pseudoatom represents one turn (about 10 basepairs) of the double helix;
 RNA structure in the ribosome and other large systems has been modeled with one pseudoatom per nucleotide.
The simplest form of coarsegraining 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 CH_{3} methyl group explicitly (or all three atoms of CH_{2} methylene group), one represents the whole group with a single pseudoatom. This pseudoatom must, of course, be properly parameterized so that its van der Waals interactions with other groups have the proper distancedependence. Similar considerations apply to the bonds, angles, and torsions in which the pseudoatom 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 forcefield.
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 pseudoatom. 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.
Steered molecular dynamics (SMD)
Steered molecular dynamics (SMD) simulations, or force probe simulations, apply forces to a protein in order to manipulate its structure by pulling it along desired degrees of freedom. These experiments can be used to reveal structural changes in a protein at the atomic level. SMD is often used to simulate events such as mechanical unfolding or stretching.^{[36]}
There are two typical protocols of SMD: one in which pulling velocity is held constant and one in which applied force is constant. Typically, part of the studied system (e.g. an atom in a protein) is restrained by a harmonic potential. Forces are then applied to specific atoms at either a constant velocity or a constant force. Umbrella sampling is used to move the system along the desired reaction coordinate by varying, for example, the forces, distances, and angles manipulated in the simulation. Through umbrella sampling, all of the system's configurations—both highenergy and lowenergy—are adequately sampled. Then, each configuration's change in free energy can be calculated as the potential of mean force.^{[37]} A popular method of computing PMF is through the weighted histogram analysis method (WHAM), which analyzes a series of umbrella sampling simulations.^{[38]}^{[39]}
Examples of applications
Molecular dynamics is used in many fields of science.
 First MD simulation of a simplified biological folding process was published in 1975. Its simulation published in Nature paved the way for the vast area of modern computational proteinfolding.^{[40]}
 First MD simulation of a biological process was published in 1976. Its simulation published in Nature paved the way for understanding protein motion as essential in function and not just accessory.^{[41]}
 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 and solid surfaces.^{[42]}^{[43]}
 MD simulations were successfully applied to predict the molecular basis of the most common protein mutation N370S, causing Gaucher Disease.^{[44]} In a followup publication it was shown that these blind predictions show a surprisingly high correlation with experimental work on the same mutant, published independently at a later point.^{[45]}
 MD simulations have been used to investigate the effect of surface charges on disjoining pressure of thin water films on metal surfaces.^{[46]}
 MD simulations are used along with multislice image simulations to understand transmission electron microscope image features ^{[47]}
The following biophysical examples illustrate notable efforts to produce simulations of a systems of very large size (a complete virus) or very long simulation times (up to 1.112 milliseconds):
 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 that 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.^{[48]}
 Folding simulations of the Villin Headpiece in allatom 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 largescale 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 realtime 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.^{[49]}
 Long continuoustrajectory simulations have been performed on Anton, a massively parallel supercomputer designed and built around custom ASICs and interconnects by D. E. Shaw Research. The longest published result of a simulation performed using Anton is a 1.112millisecond simulation of NTL9 at 355 K; a second, independent 1.073millisecond simulation of this configuration was also performed (as well as numerous additional simulations of over 250 µs continuous chemical time).^{[50]} In "How FastFolding Proteins Fold", researchers Kresten LindorffLarsen, Stefano Piana, Ron O. Dror, and David E. Shaw discuss "the results of atomiclevel molecular dynamics simulations, over periods ranging between 100 μs and 1 ms, that reveal a set of common principles underlying the folding of 12 structurally diverse proteins." Examination of these diverse long trajectories, enabled by specialized, custom hardware, allow them to conclude that "In most cases, folding follows a single dominant route in which elements of the native structure appear in an order highly correlated with their propensity to form in the unfolded state."^{[50]} In a separate study, Anton was used to conduct a 1.013millisecond simulation of the nativestate dynamics of bovine pancreatic trypsin inhibitor (BPTI) at 300 K.^{[51]}
 These molecular simulations have been used to understand the material removal mechanisms, effects of tool geometry, temperature, and process parameters such as cutting speed and cutting forces.^{[52]} It was also used to investigate the mechanisms behind the exfoliation of few layers of graphene^{[53]}^{[54]} and carbon nanoscrolls.
Molecular dynamics algorithms
Integrators
 Symplectic integrator
 VerletStoermer integration
 Runge–Kutta integration
 Beeman's algorithm
 Constraint algorithms (for constrained systems)
Shortrange interaction algorithms
 Cell lists
 Verlet list
 Bonded interactions
Longrange interaction algorithms
 Ewald summation
 Particle mesh Ewald (PME)
 Particle–particle particle mesh P3M
 Shifted force method
Parallelization strategies
 Domain decomposition method (Distribution of system data for parallel computing)
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.
Graphics card as a hardware for MD simulations
See also
 Molecular modeling
 Computational chemistry
 Force field (chemistry)
 Force field implementation
 Monte Carlo method
 Molecular design software
 Molecular mechanics
 Car–Parrinello method
 Software for molecular mechanics modeling
 Quantum chemistry
 Discrete element method
 List of nucleic acid simulation software
 Molecule editor
References
 ^ ^{a} ^{b} ^{c} Alder, B. J.; T. E. Wainwright (1959). "Studies in Molecular Dynamics. I. General Method". J. Chem. Phys. 31 (2): 459.
 ^ ^{a} ^{b} ^{c}
 ^ Schlick, T. (1996). "Pursuing Laplace's Vision on Modern Computers". In J. P. Mesirov, K. Schulten and D. W. Sumners. Mathematical Applications to Biomolecular Structure and Dynamics, IMA Volumes in Mathematics and Its Applications 82. New York: SpringerVerlag. pp. 218–247.
 ^ de Laplace, P. S. (1820). Oeuveres Completes de Laplace, Theorie Analytique des Probabilites (in French). Paris, France: GauthierVillars.
 ^ Gibson, J B; Goland, A N; Milgram, M; Vineyard, G H (1960). "Dynamics of Radiation Damage". Phys. Rev. 120: 1229–1253.
 ^ Bernal, J.D. (1964). "The Bakerian lecture, 1962: The structure of liquids". Proceedings of the Royal Society 280 (1382): 299–322.
 ^ Koehl, P.;
 ^ Raval, A; Piana, S; Eastwood, MP; Dror, RO; Shaw, DE (August 2012). "Refinement of protein structure homology models via long, allatom molecular dynamics simulations.". Proteins 80 (8): 2071–9.
 ^ Beauchamp, KA; Lin, YS; Das, R; Pande, VS (10 April 2012). "Are Protein Force Fields Getting Better? A Systematic Benchmark on 524 Diverse NMR Measurements.". Journal of chemical theory and computation 8 (4): 1409–1414.
 ^ Piana, S; Klepeis, JL; Shaw, DE (February 2014). "Assessing the accuracy of physical models used in proteinfolding simulations: quantitative evidence from long molecular dynamics simulations.". Current opinion in structural biology 24: 98–105.
 ^ Hydrophobic interactions are mostly of entropic nature at room temperature.
 ^ Myers, J. K.; Pace, C. N. (1996). "Hydrogen bonding stabilizes globular proteins". Biophys. J. 71 (4): 2033–2039.
 ^ ^{a} ^{b} Jacob Israelachvili (1992). Intermolecular and surface forces. Academic Press, San Diego.
 ^ http://www.sandia.gov/~sjplimp/md.html
 ^ Streett WB, Tildesley DJ, Saville G; Tildesley; Saville (1978). "Multiple timestep methods in molecular dynamics". Mol Phys 35 (3): 639–648.
 ^ Tuckerman ME, Berne BJ, Martyna GJ; Berne; Martyna (1991). "Molecular dynamics algorithm for multiple time scales: systems with long range forces". J Chem Phys 94 (10): 6811–6815.
 ^ Tuckerman ME, Berne BJ, Martyna GJ; Berne; Martyna (1992). "Reversible multiple time scale molecular dynamics". J Chem Phys 97 (3): 1990–2001.
 ^ Sugita, Yuji; Yuko Okamoto (1999). "Replicaexchange molecular dynamics method for protein folding". Chem Phys Letters 314: 141–151.
 ^ Sinnott, S. B.; Brenner, D. W. (2012). "Three decades of manybody potentials in materials research". MRS Bulletin 37 (5): 469–473.
 ^ Albe, K.; Nordlund, K.; Averback, R. S. (2002). "Modeling metalsemiconductor interaction: Analytical bondorder potential for platinumcarbon". Phys. Rev. B 65 (19): 195124.
 ^ Brenner, D. W. (1990). "Empirical potential for hydrocarbons for use in simulating the chemical vapor deposition of diamond films". Phys. Rev. B 42 (15): 9458–9471.
 ^ Keith Beardmore and Roger Smith. (1996) Empirical potentials for csih systems with application to C60 interactions with Si crystal surfaces. Phil. Mag. A 74:14391466.
 ^ Boris Ni, KiHo Lee, and Susan B Sinnott. (2004) A reactive empirical bond order (rebo) potential for hydrocarbon oxygen interactions. J. Phys.: Condens. Matter 16:72617275.
 ^ van Duin, A.; Siddharth Dasgupta, François Lorant and William A. Goddard III; Lorant, Francois; Goddard, William A. (2001). "ReaxFF: A Reactive Force Field for Hydrocarbons". J. Phys. Chem. A 105 (41): 9398.
 ^ Tersoff, J. (1989). "Modeling solidstate chemistry: Interatomic potentials for multicomponent systems". Phys. Rev. B 39 (8): 5566–5568.
 ^ Daw, M. S.; S. M. Foiles and M. I. Baskes (1993). "The embeddedatom method: a review of theory and applications". Mat. Sci. And Engr. Rep. 9 (7–8): 251–310.
 ^ Cleri, F.; V. Rosato (1993). "Tightbinding potentials for transition metals and alloys". Phys. Rev. B 48: 22–33.
 ^ Lamoureux G, Harder E, Vorobyov IV, Roux B, MacKerell AD; Harder; Vorobyov; Roux; MacKerell (2006). "A polarizable model of water for molecular dynamics simulations of biomolecules". Chem Phys Lett 418: 245–249.
 ^ Patel, S.; MacKerell, Jr. AD; Brooks III, Charles L (2004). "CHARMM fluctuating charge force field for proteins: II protein/solvent properties from molecular dynamics simulations using a nonadditive electrostatic model". J Comput Chem 25 (12): 1504–1514.
 ^ 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 HammesSchiffer (The Pennsylvania State University), Donald Truhlar and Jiali Gao (University of Minnesota) and Kenneth Merz (University of Florida).
 ^ Billeter, SR; SP Webb; PK Agarwal; T Iordanov; S HammesSchiffer (2001). "Hydride Transfer in Liver Alcohol Dehydrogenase: Quantum Dynamics, Kinetic Isotope Effects, and Role of Enzyme Motion". J Am Chem Soc 123 (45): 11262–11272.
 ^ Smith, A; CK Hall (2001). "AlphaHelix Formation: Discontinuous Molecular Dynamics on an IntermediateResolution Protein Model". Proteins 44 (3): 344–360.
 ^ Ding, F; JM Borreguero; SV Buldyrey; HE Stanley; NV Dokholyan (2003). "Mechanism for the alphahelix to betahairpin transition". J Am Chem Soc 53 (2): 220–228.
 ^ Paci, E; M Vendruscolo; M Karplus (2002). "Validity of Go Models: Comparison with a SolventShielded Empirical Energy Decomposition". Biophys J 83 (6): 3032–3038.
 ^ Chakrabarty, A; T Cagin (2010). "Coarse grain modeling of polyimide copolymers". Polymer 51 (12): 2786–2794.
 ^ Nienhaus, Gerd Ulrich (2005). Proteinligand interactions: methods and applications. pp. 54–56.
 ^ Leszczyński, Jerzy (2005). Computational chemistry: reviews of current trends, Volume 9. pp. 54–56.
 ^ Kumar, Shankar; Rosenberg, John M.; Bouzida, Djamal; Swendsen, Robert H.; Kollman, Peter A. (30 September 1992). "The weighted histogram analysis method for freeenergy calculations on biomolecules. I. The method". Journal of Computational Chemistry 13 (8): 1011–1021.
 ^ Bartels, Christian (1 December 2000). "Analyzing biased Monte Carlo and molecular dynamics simulations". Chemical Physics Letters 331 (5–6): 446–454.
 ^ Levitt, M; A Warshel (1975). "Computer Simulations of Protein Folding". Nature 253 (5494): 694–8.
 ^ Warshel, A (1976). "Bicyclepedal Model for the First Step in the Vision Process". Nature 260 (5553): 679–683.
 ^ Averback, R. S.; Diaz de la Rubia, T. (1998). "Displacement damage in irradiated metals and semiconductors". In H. Ehrenfest and F. Spaepen. Solid State Physics 51. New York: Academic Press. pp. 281–402.
 ^ R. Smith, ed. (1997). Atomic & ion collisions in solids and at surfaces: theory, simulation and applications. Cambridge, UK: Cambridge University Press.
 ^ Offman, MN; M Krol; I Silman; JL Sussman; AH Futerman (2010). "Molecular basis of reduced glucosylceramidase activity in the most common Gaucher disease mutant, N370S". J. Biol. Chem. 285 (53): 42105–42114.
 ^ Offman, MN; M Krol; B Rost; I Silman; JL Sussman; AH Futerman (2011). "Comparison of a molecular dynamics model with the Xray structure of the N370S acidbetaglucosidase mutant that causes Gaucher disease". Protein Eng. Des. Sel. 24 (10): 773–775.
 ^ Hu, Han; Sun, Ying. "Molecular dynamics simulations of disjoining pressure effect in ultrathin water film on a metal surface". Appl. Phys. Lett. 14: 263110.
 ^ Welch, D. A.; Mehdi, B. L.; Hatchell, H. J.; Faller, R.; Evans, J. E.; Browning, N. D. (2015). "Using molecular dynamics to quantify the electrical double layer and examine the potential for its direct observation in the insitu TEM". Advanced Structural and Chemical Imaging 1.
 ^ Freddolino P, Arkhipov A, Larson SB, McPherson A, Schulten K. "Molecular dynamics simulation of the Satellite Tobacco Mosaic Virus (STMV)". Theoretical and Computational Biophysics Group. University of Illinois at Urbana Champaign.
 ^ The Folding@Home Project and recent papers published using trajectories from it. Vijay Pande Group. Stanford University
 ^ ^{a} ^{b} LindorffLarsen, Kresten; Piana, Stefano; Dror, Ron O.; Shaw, David E. (2011). "How FastFolding Proteins Fold". Science 334 (6055): 517–520.
 ^ Shaw, David E.; Maragakis, Paul; LindorffLarsen, Kresten; Piana, Stefano; Dror, Ron O.; Eastwood, Michael P.; Bank, Joseph A.; Jumper, John M.; Salmon, John K.; et al. (2010). "AtomicLevel Characterization of the Structural Dynamics of Proteins". Science 330 (6002): 341–346.
 ^ Goel S, Luo; Reuben R L. "Molecular dynamics simulation model for the quantitative assessment of tool wear during single point diamond turning of cubic silicon carbide". Comput. Mater. Sci 51.
 ^ Jayasena, Buddhika; Subbiah Sathyan (2011). "A novel mechanical cleavage method for synthesizing fewlayer graphenes". Nanoscale Research Letters 6 (1): 95.
 ^ Jayasena, B; Reddy C.D; Subbiah S. "Separation, folding and shearing of graphene layers during wedgebased mechanical exfoliation". Nanotechnology. 24 (20): 205301.
General references
 M. P. Allen, D. J. Tildesley (1989) Computer simulation of liquids. Oxford University Press. ISBN 0198556454.
 J. A. McCammon, S. C. Harvey (1987) Dynamics of Proteins and Nucleic Acids. Cambridge University Press. ISBN 0521307503 (hardback).
 D. C. Rapaport (1996) The Art of Molecular Dynamics Simulation. ISBN 0521445612.
 J. M. Haile (2001) Molecular Dynamics Simulation: Elementary Methods. ISBN 047118439X
 R. J. Sadus, Molecular Simulation of Fluids: Theory, Algorithms and ObjectOrientation, 2002, ISBN 0444510826
 Oren M. Becker, Alexander D. Mackerell, Jr., Benoît Roux, Masakatsu Watanabe (2001) Computational Biochemistry and Biophysics. Marcel Dekker. ISBN 082470455X.
 Andrew Leach (2001) Molecular Modelling: Principles and Applications. (2nd Edition) Prentice Hall. ISBN 9780582382107.
 Tamar Schlick (2002) Molecular Modeling and Simulation. Springer. ISBN 038795404X.
 William Graham Hoover (1991) Computational Statistical Mechanics, Elsevier, ISBN 0444881921.
 D. J. Evans and G. P. Morriss (2008) Statistical Mechanics of Nonequilibrium Liquids, Second Edition, Cambridge University Press, ISBN 9780521857918.
 BouRabee, Nawaf (2014). "Time Integrators for Molecular Dynamics". Entropy (MDPI) 16 (1): 138–162.
External links
 The GPUGRID.net Project (GPUGRID.net)
 The Blue Gene Project (IBM)JawBreakers.org
 D. E. Shaw Research (D. E. Shaw Research)
 Molecular Physics
 Online course on (MSE 597G) An Introduction to Molecular Dynamics by Alejandro Strachan
 Ashlie Martini (2009)Short Course on Molecular Dynamics SimulationLecture Notes on
 Materials modelling and computer simulation codes
 A few tips on molecular dynamics
 Molecular dynamics simulation methods revised
 Movie of MD simulation of water (Youtube)