title: Force-Field Development and Molecular Dynamics of [NiFe] Hydrogenase.
abstract: Classical molecular force-field parameters describing the structure and motion of metal clusters in [NiFe] hydrogenase enzymes can be used to compare the dynamics and thermodynamics of [NiFe] under different oxidation, protonation, and ligation circumstances. Using density functional theory (DFT) calculations of small model clusters representative of the active site and the proximal, medial, and distal Fe/S metal centers and their attached protein side chains, we have calculated classical force-field parameters for [NiFe] in reduced and oxidized states, including internal coordinates, force constants, and atom-centered charges. Derived force constants revealed that cysteinate ligands bound to the metal ions are more flexible in the Ni-B active site, which has a bridging hydroxide ligand, than in the Ni-C active site, which has a bridging hydride. Ten nanosecond all-atom, explicit-solvent MD simulations of [NiFe] hydrogenase in oxidized and reduced catalytic states established the stability of the derived force-field parameters in terms of Cα and metal cluster fluctuations. Average active site structures from the protein MD simulations are consistent with [NiFe] structures from the Protein Data Bank, suggesting that the derived force-field parameters are transferrable to other hydrogenases beyond the structure used for testing. A comparison of experimental H2-production rates demonstrated a relationship between cysteinate side chain rotation and activity, justifying the use of a fully dynamic model of [NiFe] metal cluster motion.
authors.affiliation: Pacific Northwest National Laboratory, P.O. Box 999, MSIN J4-33, Richland, Washington 99352, United States.
authors.forename: Dayle M A
authors.initials: DM
authors.lastname: Smith
authors.affiliation: Pacific Northwest National Laboratory, P.O. Box 999, MSIN J4-33, Richland, Washington 99352, United States.
authors.forename: Yijia
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Pacific Northwest National Laboratory, P.O. Box 999, MSIN J4-33, Richland, Washington 99352, United States.
authors.forename: T P
authors.initials: TP
authors.lastname: Straatsma
authors.affiliation: Pacific Northwest National Laboratory, P.O. Box 999, MSIN J4-33, Richland, Washington 99352, United States.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Rosso
authors.affiliation: Pacific Northwest National Laboratory, P.O. Box 999, MSIN J4-33, Richland, Washington 99352, United States.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Squier