Dynamics of methionine ligand rebinding in cytochrome c
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Geminate recombination of the methionine ligand to heme iron in ferrous cytochrome c protein following photodissociation displays rich kinetics. It is of particular interest to develop an understanding of fast and slow rebinding timescales, observed in experimental studies, in terms of features of the protein's underlying energy landscape. To accurately model this complex molecular system, the classical empirical force field for the protein and solvent has been extended by incorporating information from ab initio potential energy surface calculations. An algorithm based on the Landau-Zener non-adiabatic transition theory has been developed and implemented into an otherwise classical molecular dynamics simulation model to allow for electronic surface hopping between the singlet and the quintet states, critical to the dissociation and rebinding transitions. Multiple conformational substates of the dissociated methionine are found to participate in the reaction dynamics. Varying timescales for the experimentally observed fast and slow ligand rebinding are elucidated through a mechanism based on the underlying dynamics of interconversion between conformational substates. A two-dimensional reaction coordinate that captures the essential protein dynamics is proposed. Temperature and solvent dependence of the methionine ligand rebinding in cytochrome c has been studied. Conformational substates of methionine, observed at high temperature and found to be critical to the high temperature rebinding dynamics, are not observed during the process of dissociation and rebinding at low temperature or in high viscosity conditions. The activation energy for transitions between substates is estimated through its temperature dependence. A higher energetic barrier at lower temperature leads to a lower reaction rate. The distinctive rebinding kinetics and the reaction paths at low temperature suggest that the rebinding dynamics are dictated by the conformational substates accessible to the protein prior to photodissociation. The more single-exponential like nature of the kinetics at higher temperature is attributed to the protein conformational homogeneity. Insight into the reaction dynamics derived from these simulations has led to suggestions for future experiments to further probe the role of dynamic heterogeneity in the kinetics of function-related ligand-protein binding.
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