title: Accurate Estimation of Protein Folding and Unfolding Times: Beyond Markov State Models.
abstract: Because standard molecular dynamics (MD) simulations are unable to access time scales of interest in complex biomolecular systems, it is common to "stitch together" information from multiple shorter trajectories using approximate Markov state model (MSM) analysis. However, MSMs may require significant tuning and can yield biased results. Here, by analyzing some of the longest protein MD data sets available (>100 μs per protein), we show that estimators constructed based on exact non-Markovian (NM) principles can yield significantly improved mean first-passage times (MFPTs) for protein folding and unfolding. In some cases, MSM bias of more than an order of magnitude can be corrected when identical trajectory data are reanalyzed by non-Markovian approaches. The NM analysis includes "history" information, higher order time correlations compared to MSMs, that is available in every MD trajectory. The NM strategy is insensitive to fine details of the states used and works well when a fine time-discretization (i.e., small "lag time") is used.
authors.affiliation: Department of Computational and Systems Biology, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Suárez
authors.affiliation: Department of Biological Sciences, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Adelman
authors.affiliation: Department of Computational and Systems Biology, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Zuckerman
mesh_terms: D029681:Arabidopsis Proteins / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008390:Markov Chains; D008840:Microfilament Proteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D017510:Protein Folding; D058767:Protein Unfolding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism
chemical_list: D029681:Arabidopsis Proteins; D008840:Microfilament Proteins; C531121:NTL9 protein, Arabidopsis; D009842:Oligopeptides; D010455:Peptides; D011506:Proteins; D014157:Transcription Factors; C508725:Trp-cage peptide; C506175:chignolin; C026615:villin