title: Computation of Rate Constants for Diffusion of Small Ligands to and from Buried Protein Active Sites.
abstract: The diffusion of ligands to actives sites of proteins is essential to enzyme catalysis and many cellular signaling processes. In this contribution we review our recently developed methodology for calculation of rate constants for diffusion and binding of small molecules to buried protein active sites. The diffusive dynamics of the ligand obtained from molecular dynamics simulation is coarse grained and described by a Markov state model. Diffusion and binding rate constants are then obtained either from the reactive flux formalism or by fitting the time-dependent population of the Markov state model to a phenomenological rate law. The method is illustrated by applications to diffusion of substrate and inhibitors in [NiFe] hydrogenase, CO-dehydrogenase, and myoglobin. We also discuss a recently developed sensitivity analysis that allows one to identify hot spots in proteins, where mutations are expected to have the strongest effects on ligand diffusion rates.
authors: RIKEN Theoretical Molecular Science Laboratory, Wako-shi, Saitama, Japan.
authors: P-H
authors: PH
authors: Wang
authors: CIC NanoGUNE, Donostia-San Sebastián, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
authors: D
authors: D
authors: De Sancho
authors: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States.
authors: R B
authors: RB
authors: Best
authors: University College London, London, United Kingdom. Electronic address: j.blumberger@ucl.ac.uk.
authors: J
authors: J
authors: Blumberger
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000737:chemistry* / Q000235:genetics; D001665:Binding Sites; D055162:Biocatalysis; D020134:Catalytic Domain; D000068016:Eubacteriales / Q000737:chemistry / Q000201:enzymology; D016000:Cluster Analysis; D045286:Desulfovibrio gigas / Q000737:chemistry / Q000201:enzymology; D004058:Diffusion; D006801:Humans; D006864:Hydrogenase / Q000737:chemistry* / Q000235:genetics; D007700:Kinetics; D008024:Ligands; D008390:Markov Chains; D056004:Molecular Dynamics Simulation; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000235:genetics; D009154:Mutation; D009211:Myoglobin / Q000737:chemistry* / Q000235:genetics; D011485:Protein Binding; D013816:Thermodynamics
chemical_list: D008024:Ligands; D009097:Multienzyme Complexes; D009211:Myoglobin; C043296:nickel-iron hydrogenase; D006864:Hydrogenase; D000445:Aldehyde Oxidoreductases; C019823:carbon monoxide dehydrogenase
keywords: Kinetics; Ligand diffusion; Molecular dynamics simulation; Rate