title: Identification of Mutational Hot Spots for Substrate Diffusion: Application to Myoglobin.
abstract: The pathways by which small molecules (substrates or inhibitors) access active sites are a key aspect of the function of enzymes and other proteins. A key problem in designing or altering such proteins is to identify sites for mutation that will have the desired effect on the substrate transport properties. While specific access channels have been invoked in the past, molecular simulations suggest that multiple routes are possible, complicating the analysis. This complexity, however, can be captured by a Markov State Model (MSM) of the ligand diffusion process. We have developed a sensitivity analysis of the resulting rate matrix, which identifies the locations where mutations should have the largest effect on the diffusive on rate. We apply this method to myoglobin, which is the best characterized example both from experiment and simulation. We validate the approach by translating the sensitivity parameter obtained from this method into the CO binding rates in myoglobin upon mutation, resulting in a semi-quantitative correlation with experiments. The model is further validated against an explicit simulation for one of the experimental mutants.
authors.affiliation: Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, United Kingdom.|CIC nanoGUNE , Tolosa Hiribidea 76, 20018 Donostia-San Sebastian, Spain.|IKERBASQUE, Basque Foundation for Science , Maria Diaz de Haro 3, 48013 Bilbao, Spain.
authors.forename: David
authors.initials: D
authors.lastname: De Sancho
authors.affiliation: Department of Physics and Astronomy, University College London , Gower Street, London WC1E 6BT, United Kingdom.
authors.forename: Adam
authors.initials: A
authors.lastname: Kubas
authors.affiliation: Department of Physics and Astronomy, University College London , Gower Street, London WC1E 6BT, United Kingdom.|Theoretical Molecular Science Laboratory , 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
authors.forename: Po-Hung
authors.initials: PH
authors.lastname: Wang
authors.affiliation: Department of Physics and Astronomy, University College London , Gower Street, London WC1E 6BT, United Kingdom.
authors.forename: Jochen
authors.initials: J
authors.lastname: Blumberger
authors.affiliation: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland 20892-0520, United States.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Best
mesh_terms: D001665:Binding Sites; D002248:Carbon Monoxide / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D004058:Diffusion; D008390:Markov Chains; D056004:Molecular Dynamics Simulation; D016296:Mutagenesis; D009211:Myoglobin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D009211:Myoglobin; D002248:Carbon Monoxide