Ab Initio Evaluation of the Redox Potential of Cytochrome c

Various biochemical activities of metabolism and biosynthesis are fulfilled by redox processes with explicit electron exchange, which furnish redox enzymes with high chemical reactivity. However, theoretical investigation of a redox process, which simultaneously involves a complex electronic change at a redox metal center and conformational reorganization of the surrounding protein environment coupled to the electronic change, requires computationally conflicting approaches, highly accurate quantum chemical calculations, and long-time molecular dynamics (MD) simulations, limiting the physicochemical understanding of biological redox processes. Here, we theoretically examined a redox process of cytochrome c by means of a hybrid molecular simulation technique, which enables one to consistently treat the redox center at the ab initio quantum chemistry level of theory and the protein reorganization with long-time MD simulations on the microsecond timescale. The calculations successfully evaluated a large absolute redox potential, 4.34 eV, with errors of only 0.03 to 0.34 eV to the experimental ones without any problem-specific empirical parameters. Through the long-time MD sampling, large and nonlinear reorganization of the protein environment was unveiled and the molecular determinants for the redox potential were identified. The present ab initio approach significantly expands the applicability of theoretical investigation to biological redox systems with more electronically complicated redox centers such as polynuclear transition metal complexes.