Jump to main content
Jump to site search
PLANNED MAINTENANCE Close the message box

Scheduled maintenance work on Wednesday 22nd May 2019 from 11:00 AM to 1:00 PM (GMT).

During this time our website performance may be temporarily affected. We apologise for any inconvenience this might cause and thank you for your patience.


Issue 24, 2012
Previous Article Next Article

Will molecular dynamics simulations of proteins ever reach equilibrium?

Author affiliations

Abstract

We show that conformational entropies calculated for five proteins and protein–ligand complexes with dihedral-distribution histogramming, the von Mises approach, or quasi-harmonic analysis do not converge to any useful precision even if molecular dynamics (MD) simulations of 380–500 ns length are employed (the uncertainty is 12–89 kJ mol−1). To explain this, we suggest a simple protein model involving dihedrals with effective barriers forming a uniform distribution and show that for such a model, the entropy increases logarithmically with time until all significantly populated dihedral states have been sampled, in agreement with the simulations (during the simulations, 52–70% of the available dihedral phase space has been visited). This is also confirmed by the analysis of the trajectories of a 1 ms simulation of bovine pancreatic trypsin inhibitor (31 kJ mol−1 difference in the entropy between the first and second part of the simulation). Strictly speaking, this means that it is practically impossible to equilibrate MD simulations of proteins. We discuss the implications of such a lack of strict equilibration of protein MD simulations and show that ligand-binding free energies estimated with the MM/GBSA method (molecular mechanics with generalised Born and surface-area solvation) vary by 3–15 kJ mol−1 during a 500 ns simulation (the higher estimate is caused by rare conformational changes), although they involve a questionable but well-converged normal-mode entropy estimate, whereas free energies estimated by free-energy perturbation vary by less than 0.6 kJ mol−1 for the same simulation.

Graphical abstract: Will molecular dynamics simulations of proteins ever reach equilibrium?

Back to tab navigation

Supplementary files

Publication details

The article was received on 12 Dec 2011, accepted on 16 Apr 2012 and first published on 17 Apr 2012


Article type: Paper
DOI: 10.1039/C2CP23961B
Phys. Chem. Chem. Phys., 2012,14, 8662-8677

  •   Request permissions

    Will molecular dynamics simulations of proteins ever reach equilibrium?

    S. Genheden and U. Ryde, Phys. Chem. Chem. Phys., 2012, 14, 8662
    DOI: 10.1039/C2CP23961B

Search articles by author

Spotlight

Advertisements