title: Dewetting of S1-Pocket via Water Channel upon Thrombin-Substrate Association Reaction.
abstract: Upon protein-substrate association reaction, dewetting of the substrate-binding pocket is one of the rate-limiting processes. However, understanding the microscopic mechanism still remains challenging because of practical limitations of experimental methodologies. We have addressed the problem here by using molecular dynamics (MD) simulation of the thrombin-substrate association reaction. During the MD simulation, ArgP1 in a substrate accessed thrombin's substrate-binding pocket and formed specific hydrogen bonds (H-bonds) with Asp189 in thrombin, while the catalytic serine of thrombin was still away from the substrate's active site. It is assumed that the thrombin-substrate association reaction is regulated by a stepwise mechanism. Furthermore, in the earlier stage of ArgP1 access to the pocket, we observed that ArgP1 was spatially separated from Asp189 by two water molecules in the pocket. These water molecules transferred from the pocket, followed by the specific H-bond formation between thrombin and the substrate. Interestingly, they were not evacuated directly from the pocket to the bulk solvent, but moved to the water channel of thrombin. This observation indicates that the channel plays functional roles in dewetting upon the association reaction.
authors.affiliation: Graduate School of Information Science, Nagoya University , Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.|Core Research for Evolutional Science and Technology, Japan Science and Technology Agency , Honmachi, Kawaguchi 332-0012, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kurisaki
authors.affiliation: Graduate School of Information Science, Nagoya University , Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.|Core Research for Evolutional Science and Technology, Japan Science and Technology Agency , Honmachi, Kawaguchi 332-0012, Japan.
authors.forename: Chantal
authors.initials: C
authors.lastname: Barberot
authors.affiliation: Graduate School of Information Science, Nagoya University , Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.|Core Research for Evolutional Science and Technology, Japan Science and Technology Agency , Honmachi, Kawaguchi 332-0012, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Takayanagi
authors.affiliation: Graduate School of Information Science, Nagoya University , Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.|Core Research for Evolutional Science and Technology, Japan Science and Technology Agency , Honmachi, Kawaguchi 332-0012, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Nagaoka
mesh_terms: D056004:Molecular Dynamics Simulation; D013379:Substrate Specificity; D013917:Thrombin / Q000737:chemistry* / Q000378:metabolism; D014867:Water / Q000737:chemistry* / Q000378:metabolism; D017155:Wettability
chemical_list: D014867:Water; D013917:Thrombin