"Everything that living things do can be understood in terms of the jiggling and wiggling of atoms.", Richard Feynman, 1963.
By giving a frozen image of macromolecules structure, X-ray crystallography, and to a less extent NMR techniques, often lead to the incorrect idea that macromolecules are rigid systems. However, the function of a macromolecule is intrinsically linked to atom movements, like during an enzymatic reaction, the conformational rearrangement of a protein upon association, or the transfer of small molecules through the membranes in the context of porins, for examples.
Molecular Dynamics (MD) simulations makes use of the Newton's equation of law and rigorous statistical mechanics equation to simulate the motions of all atoms in the systems as a function of time at room temperature, in aqueous solution. Therefore, MD probes the relationship between molecular structure, movement and function.
MD simulation of the Wy-14,643 ligand in complex with xPPARα.
One major limitation in the use of MD simulations comes from the CPU cost. Typically, simulating the motions exhibited during a few nanoseconds by a large protein in water requires several days, or even years, of CPU. Although such calculations may be performed using several CPUs working together, decreasing roughly the simulation time by the same amount, this may still limit what can be done routinely. Techniques, like stochastic boundary conditions, can be used to limit the region studied by MD simulation, if one is only interested in the motions of a fraction of the macromolecule. Thus, the feasibility of MD simulations submitted by the PMF users will have to be evaluated in view of the size of the system and that of the region of interest.
Another limitation of MD simulations concerns the availability of a good starting conformation for the macromolecule. MD simulations should only be applied to systems for which an experimental structure is available, or for which a reliable homology model can be obtained.
Finally, MD simulations are not expected to reproduce large conformational rearrangement that could be expected from a drastic mutation for instance. However, in some cases, this technique can provide information about the stability of the native fold upon mutation, pointing residues that can have a large impact on the protein conformation if mutated, for example.