“Strange Kinetics” in the Temperature Dependence of Methionine Ligand Rebinding Dynamics in Cytochrome c

Abstract

The temperature dependence of methionine ligand dissociation and rebinding dynamics in cytochrome c in aqueous solution has been studied using classical molecular dynamics simulation. Results are compared with previous study of rebinding dynamics at 300 K in water in order to understand how the change of protein environment and the underlying protein energy landscape influence the dynamics. Rebinding dynamics at 77, 180, and 300 K exhibits changes in both time scale and mechanism as the protein and solvent undergo a dynamic "glass transition". At each temperature, the rebinding dynamics yields a subset of trajectories that undergo fast rebinding as well as a subset of trajectories that undergo slower rebinding. At 300 K in water, both a fast (4.0 ps) and slow (14.6 ps) rebinding is observed. While fast rebinding occurs from a "downward" (heme pointing) substate of the methionine, the slow rebinding involves interconversion between an "upward" substate, from which rebinding cannot occur, and the downward substate. At lower temperatures (77 and 180 K), the upward dissociated substate was not observed due to the high barrier imposed by the "frozen" protein structure. However, a slow rebinding phase is observed at both 77 and 180 K and is associated with a process of trapping in downward but "binding forbidden" substates with subsequent slow dynamical conversion to "binding competent" substates from which rebinding is relatively rapid. Distinctive rebinding dynamics at 77 and 180 K suggest that different rebinding time scales are predetermined by the protein and solvent structural arrangement prior to photodissociation, which causes either fast rebinding (about 2 ps) or slow (>50 ps) rebinding. Suggestions for future experiments to further probe the role of dynamic heterogeneity in the kinetics of methionine ligand binding in cytochrome c protein are proposed.