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Simulating redox coupled proton transfer in cytochrome c oxidase: Looking for the proton bottleneck
Author(s) -
Olsson Mats H.M.,
Sharma Pankaz K.,
Warshel Arieh
Publication year - 2005
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2005.02.051
Subject(s) - proton , gating , redox , chemistry , bottleneck , chemical physics , proton transport , kinetics , electron transfer , work (physics) , cytochrome c oxidase , physics , thermodynamics , computer science , biophysics , nuclear physics , quantum mechanics , biochemistry , organic chemistry , mitochondrion , biology , embedded system
Gaining a detailed understanding of the molecular nature of the redox coupled proton transfer in cytochrome c oxidase (COX) is one of the challenges of modern biophysics. The present work addresses this by integrating approaches for simulations of proton transport (PTR) and electron transfer (ET). The resulting method converts the electrostatic energies of different charge configurations and reorganization energies to free‐energy profiles for different PTR and ET pathways. This approach provides for the first time a tool to study the actual activation barriers and kinetics of different feasible PTR processes in the cycle of COX. Using this tool, we explore the PTR through the bottleneck water molecules. It is found that a stepwise PTR along this commonly assumed path leads to far too high barriers and is, thus, inconsistent with the observed kinetics. Furthermore, the simulated free‐energy profile does not provide a simple gating mechanism. Fortunately, we obtain reasonable kinetics when we consider a PTR that involves a concerted transfer of protons to and from E286. Finally, semi‐qualitative considerations of the forward and backward barriers point toward open questions about the actual gating process and offer a feasible pumping mechanism. Although further studies are clearly needed, we believe that our approach offers a general and effective tool for correlating the structure of COX with its function.