Towards fast, rigorous and efficient conformational sampling of biomolecules: Advances in accelerated molecular dynamics

• Published in: Biochimica et biophysica acta 2015-05, Vol.1850 (5), p.878-888
• Main Authors: Doshi, Urmi, Hamelberg, Donald
• Format: Article
• Language: English
• Subjects: Accelerated molecular dynamics; Chignolin; Enhanced sampling; Kinetics; Molecular Docking Simulation; Molecular Dynamics Simulation; Pharmaceutical Preparations - chemistry; Protein Conformation; Protein Folding; Protein Unfolding; Proteins - chemistry; Structure-Activity Relationship; Thermodynamics; Trp-cage; Villin headpiece
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2014.08.003

Accelerated molecular dynamics (aMD) has been proven to be a powerful biasing method for enhanced sampling of biomolecular conformations on general-purpose computational platforms. Biologically important long timescale events that are beyond the reach of standard molecular dynamics can be accessed without losing the detailed atomistic description of the system in aMD. Over other biasing methods, aMD offers the advantages of tuning the level of acceleration to access the desired timescale without any advance knowledge of the reaction coordinate. Recent advances in the implementation of aMD and its applications to small peptides and biological macromolecules are reviewed here along with a brief account of all the aMD variants introduced in the last decade. In comparison to the original implementation of aMD, the recent variant in which all the rotatable dihedral angles are accelerated (RaMD) exhibits faster convergence rates and significant improvement in statistical accuracy of retrieved thermodynamic properties. RaMD in conjunction with accelerating diffusive degrees of freedom, i.e. dual boosting, has been rigorously tested for the most difficult conformational sampling problem, protein folding. It has been shown that RaMD with dual boosting is capable of efficiently sampling multiple folding and unfolding events in small fast folding proteins. RaMD with the dual boost approach opens exciting possibilities for sampling multiple timescales in biomolecules. While equilibrium properties can be recovered satisfactorily from aMD-based methods, directly obtaining dynamics and kinetic rates for larger systems presents a future challenge. This article is part of a Special Issue entitled Recent developments of molecular dynamics. •We review advances in accelerated molecular dynamics, an enhanced sampling method.•The new variant of this method is more efficient and accurate than the original one.•Original equilibrium and kinetic properties can be recovered by reweighting.•RaMD with dual boosting is tested for protein folding, a difficult sampling problem.•Recent variants open new possibilities to sample long timescale biochemical events.