What Is Molecular Dynamics? How MD Simulation Works

Molecular dynamics in one paragraph

A molecular dynamics simulation takes a 3D model of a molecular system, for example a protein with a drug candidate in a box of water, and calculates how every atom moves. It does this in tiny steps of a few femtoseconds. At each step it works out the force on every atom, moves the atoms a little, and repeats the cycle millions of times. The saved positions form a movie of the molecules, called a trajectory, which you can measure and analyze.

How an MD simulation works

A starting structure. A crystal structure, a docked pose or a predicted model, with every atom and hydrogen in place.
A force field. Equations and parameters that give the energy and the force on every atom from the positions of all the others. See force field.
Newton's equations. Force gives acceleration, acceleration changes velocity and velocity changes position. The program integrates this with a time step of 2 to 4 femtoseconds.
Temperature and pressure control. A thermostat and a barostat keep the system at body temperature and atmospheric pressure so that it behaves like a real solution.
Sampling. The simulation runs for nanoseconds to microseconds and writes the positions at regular intervals.

What MD is used for

Checking a docking pose. If a ligand leaves the pocket within a few nanoseconds, the docked pose was probably wrong. If it stays and keeps its hydrogen bonds, the pose is more believable.
Protein flexibility. Which loops move, which residues are rigid and how the pocket changes shape.
Interaction lifetimes. How long each hydrogen bond, salt bridge and hydrophobic contact survives.
Binding energy estimates. MM/PBSA and MM/GBSA rank ligands from the snapshots of a trajectory.
Hidden pockets. Cryptic and allosteric pockets that open only during motion.
Mechanisms. Unbinding paths, conformational changes and the effect of a mutation.

What you measure afterwards

The standard analyses are RMSD for stability, RMSF for flexibility, radius of gyration for compactness, hydrogen bond occupancy, SASA, principal component analysis with a free energy landscape, dynamic cross correlation and MM/PBSA energies with per residue decomposition. Each of these is explained in the glossary, and the step by step guide shows what to look for.

How long does an MD simulation take?

A typical protein ligand system has 50,000 to 150,000 atoms including water. On one modern GPU it runs at roughly 50 to 300 ns per day depending on its size. A 100 ns run for one complex therefore takes between several hours and a couple of days. On a CPU only it would take weeks, which is why MD is done on GPUs. Three independent replicates of 100 ns are a common standard for a paper.

What MD cannot do

It cannot reach long timescales. Most simulations are nanoseconds to microseconds, while binding and large conformational changes can take far longer.
It is only as good as its force field and its starting structure. A wrong protonation state or ligand charge gives wrong dynamics.
One simulation is one example. Without replicates you cannot say whether a result is reproducible.
MM/PBSA gives a ranking, not an exact binding free energy.

Programs people use

GROMACS and OpenMM are open source, AMBER and NAMD are widely used in academia, and CHARMM-GUI builds input files from a web page. Analysis is often done with MDAnalysis or VMD.

Molecular dynamics, docking and DFT compared

Method	What it treats	Typical question
Molecular docking	A rigid or lightly flexible receptor, many ligands, a score per pose	Which molecules fit this pocket and how?
Molecular dynamics	Every atom moving in water over nanoseconds, with a force field	Does the complex stay bound and what moves?
DFT	The electrons of one molecule or a small cluster	What are its orbitals, charges, spectra and reaction energies?

How to do an MD simulation

The short version is to prepare a clean complex, pick a force field, add water and ions, minimize the energy, equilibrate in NVT and NPT, run production and analyze the trajectory. Each step has its settings explained in how to do a molecular dynamics simulation, step by step. If you start from a docking result, first dock and validate your ligand.

Run molecular dynamics on ChemServer

ChemServer does molecular dynamics simulation online on request. Email chris@chemserver.online with your protein, your ligand as SMILES and the length you want, and the run is set up on a GPU compute server with the analysis above.

What is molecular dynamics?