In-silico Assessment of Protein-Protein Electron Transfer. A Case Study: Cytochrome c Peroxidase – Cytochrome c

The fast development of software and hardware is notably helping in closing the gap between macroscopic and microscopic data. Using a novel theoretical strategy combining molecular dynamics simulations, conformational clustering, ab-initio quantum mechanics and electronic coupling calculations, we show how computational methodologies are mature enough to provide accurate atomistic details into the mechanism of electron transfer (ET) processes in complex protein systems, known to be a significant challenge. We performed a quantitative study of the ET between Cytochrome c Peroxidase and its redox partner Cytochrome c. Our results confirm the ET mechanism as hole transfer (HT) through residues Ala194, Ala193, Gly192 and Trp191 of CcP. Furthermore, our findings indicate the fine evolution of the enzyme to approach an elevated turnover rate of 5.47Ã106 sâ1 for the ET between Cytc and CcP through establishment of a localized bridge state in Trp191. We have developed a protocol capable of describing long-range electron transfer mechanisms at an atomic detailed level. We demonstrate the maturity of the computational techniques in obtaining a quantitative view of the Cytochrome c Peroxidase/Cytochrome c electron transfer process, known to be a significant challenge. In excellent agreement with experimental data, our results allow for the description of the electron transfer pathway, its mechanism and the electron transfer rate at a quantitative level. The overall protocol is free of parameterization and can be applied to any complex electron transfer process. Furthermore, the results reveal the fine enzyme evolution of this protein-protein complex to optimize its electron transfer rate by a localized bridge state.