title: Kinetic distance and kinetic maps from molecular dynamics simulation.
abstract: Characterizing macromolecular kinetics from molecular dynamics (MD) simulations requires a distance metric that can distinguish slowly interconverting states. Here, we build upon diffusion map theory and define a kinetic distance metric for irreducible Markov processes that quantifies how slowly molecular conformations interconvert. The kinetic distance can be computed given a model that approximates the eigenvalues and eigenvectors (reaction coordinates) of the MD Markov operator. Here, we employ the time-lagged independent component analysis (TICA). The TICA components can be scaled to provide a kinetic map in which the Euclidean distance corresponds to the kinetic distance. As a result, the question of how many TICA dimensions should be kept in a dimensionality reduction approach becomes obsolete, and one parameter less needs to be specified in the kinetic model construction. We demonstrate the approach using TICA and Markov state model (MSM) analyses for illustrative models, protein conformation dynamics in bovine pancreatic trypsin inhibitor and protein-inhibitor association in trypsin and benzamidine. We find that the total kinetic variance (TKV) is an excellent indicator of model quality and can be used to rank different input feature sets.
authors.affiliation: FU Berlin , Department of Mathematics, Computer Science and Bioinformatics, Arnimallee 6, 14195 Berlin, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Noé
authors.affiliation: Center for Theoretical Biological Physics, and Department of Chemistry, Rice University , Houston, Texas 77005, United States.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Clementi
mesh_terms: D000818:Animals; D001550:Benzamidines / Q000737:chemistry* / Q000494:pharmacology; D002417:Cattle; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D010179:Pancreas / Q000201:enzymology; D013329:Structure-Activity Relationship; D014357:Trypsin / Q000737:chemistry* / Q000378:metabolism; D014361:Trypsin Inhibitors / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D001550:Benzamidines; D014361:Trypsin Inhibitors; D014357:Trypsin; C032157:benzamidine