Computing ensembles of transitions from stable states: Dynamic importance sampling.
There is an increasing dataset of solved biomolecular structures in more than one conformation and increasing evidence that large-scale conformational change is critical for biomolecular function. In this article, we present our implementation of a dynamic importance sampling (DIMS) algorithm that is directed toward improving our understanding of important intermediate states between experimentally defined starting and ending points. This complements traditional molecular dynamics methods where most of the sampling time is spent in the stable free energy wells defined by these initial and final points. As such, the algorithm creates a candidate set of transitions that provide insights for the much slower and probably most important, functionally relevant degrees of freedom. The method is implemented in the program CHARMM and is tested on six systems of growing size and complexity. These systems, the folding of Protein A and of Protein G, the conformational changes in the calcium sensor S100A6, the glucose-galactose-binding protein, maltodextrin, and lactoferrin, are also compared against other approaches that have been suggested in the literature. The results suggest good sampling on a diverse set of intermediates for all six systems with an ability to control the bias and thus to sample distributions of trajectories for the analysis of intermediate states.
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. jrperillaj@jhu.edu
Juan R
JR
Perilla
Oliver
O
Beckstein
Elizabeth J
EJ
Denning
Thomas B
TB
Woolf
D000465:Algorithms; D000818:Animals; D002135:Calcium-Binding Proteins / Q000737:chemistry; D018797:Cell Cycle Proteins / Q000737:chemistry; D006801:Humans; D007781:Lactoferrin / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D009004:Monosaccharide Transport Proteins / Q000737:chemistry; D009419:Nerve Tissue Proteins / Q000737:chemistry; D033902:Periplasmic Binding Proteins / Q000737:chemistry; D011134:Polysaccharides / Q000737:chemistry; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry*; D000075383:S100 Calcium Binding Protein A6; D009418:S100 Proteins / Q000737:chemistry; D013205:Staphylococcal Protein A / Q000737:chemistry; D013816:Thermodynamics
D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; C029152:G-substrate; D009004:Monosaccharide Transport Proteins; D009419:Nerve Tissue Proteins; D033902:Periplasmic Binding Proteins; D011134:Polysaccharides; D011506:Proteins; D000075383:S100 Calcium Binding Protein A6; D009418:S100 Proteins; D013205:Staphylococcal Protein A; C023550:galactose-binding protein; C055351:S100A6 protein, human; C008315:maltodextrin; D007781:Lactoferrin