Molecular Dynamics


Molecular dynamics (MD) is a widely used technique for computer simulation of complex systems, modelled at the atomic or some coarse‐grained level. In this article, basic concepts pertaining to MD simulations are systematically introduced and related to the underlying models of physical systems. The principles of the atomic force fields, representation of the environment, the time evolution of the system, as well as the derivation of kinetic and thermodynamic properties of interest from MD trajectories are discussed. Applications of MD to biological systems are illustrated by examples of large scale studies on protein structure and dynamics, protein–protein interactions, and drug design. Limitations and several recent extensions of classical MD, including Replica Exchange and Steered MD, are discussed in the context of applications to biological systems as well. Related simulation protocols, including Monte Carlo and free energy methods, are summarized, highlighting complementarity and common principles of these molecular simulation approaches.

Key Concepts

  • Computer simulations can be used to facilitate and complement experimental studies of biomolecular systems.

  • Empirical force fields describe interatomic interactions in the system and enable efficient computation of forces in MD simulations.

  • MD is routinely used to study biological macromolecules and their environment.

  • A physical quantity can be measured using MD simulations by taking an arithmetic average over instantaneous values of that quantity obtained from MD trajectories.

  • Other simulation methods, such as Monte Carlo, enhanced sampling and free energy methods, are often being used in conjunction with MD and its extensions.

  • Slow processes can be studied computing the relative free energies of different states.

  • MD and related methods can be applied to systems comprising millions of atoms, providing unique insights into complex biological systems.

Keywords: molecular simulations; force field; Monte Carlo; protein dynamics; steered molecular dynamics; replica exchange molecular dynamics

Figure 1.

Conformational ensemble of ubiquitin (PDB code 2K39). Secondary structures and relative solvent accessibility (a), as well as 3D rendering of individual models (b), obtained using the POLYVIEW‐3D server (Porollo and Meller, ) are shown for randomly selected 50 models from the ensemble. The secondary structures are shown using the following colour coding :: red – helix, green – extended strand, dark green – beta‐bridge, blue – coil, violet – hydrogen bonded turn and light blue – bend. The relative solvent accessibility is shown using shaded boxes (black corresponds to fully buried, whereas white to fully exposed residues). Note also that these individual models could be interpreted as snapshots taken during MD simulations of ubiquitin in solution, effectively representing an MD trajectory of the system. Note also that the highly flexible C‐terminus of ubiquitin adopts a certain conformation upon binding to ubiquitin‐associated protein (PDB code 2JY6, (c)).

Figure 2.

Simulation model of the satellite tobacco mosaic (STM) virus (based on the PDB code 1A34) in aqueous solution. The virion is placed into a box with water molecules and periodic boundary conditions are employed to define the implicit lattice copies of the simulation box. MD simulations of fully solvated large systems such as STM virus, comprising capsid proteins (shown in yellow), RNA molecules (shown in red in panel b), counter‐ions and explicit water molecules are becoming feasible, as illustrated by this and other studies.

Figure 3.

Schematic representation of the replica exchange method using five copies of the system (replicas) simulated at different temperatures. Colour coding indicates temperatures used for individual copies, with blue and red corresponding to the lowest and highest temperature, respectively.

Figure 4.

Example of an application of the SMD method to study the properties of an elastomeric protein from insects, called resilin. Three models with different extensions obtained as a result of applying harmonic pulling force, as indicated in (b), are shown (Petrenko R, Dickerson M, Naik R et al. (2009) Entropic force in Drosophila resilin: molecular dynamics study. BIOCOMP, pp. 598–603).

Figure 5.

The ATP‐hydrolysed state of GroEL–GroES complex (PDB code 1AON, Xu et al., ), with GroEL shown in blue and green, and GroES in red. A four helical bundle, representing the folding substrate from the study by Stan et al., is shown inside the GroEL cavity, which is capped by a dome‐shaped subunit of GroES. Picture generated using POLYVIEW‐3D.



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Further Reading

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Yang Z, Majek P and Bahar I (2009) Allosteric transitions of supramolecular systems explored by network models: application to chaperonin GroEL. PLoS Computational Biology 5: e1000360.

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Petrenko, Roman, and Meller, Jarosław(Mar 2010) Molecular Dynamics. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0003048.pub2]