Charge Transfer and Chemo-Mechanical Coupling in Respiratory Complex I

Abstract

The mitochondrial respiratory chain formed by five protein complexes utilizes energy from catabolic processes to synthesize ATP. Complex I, the first and the largest protein complex of the chain, harvests electrons from NADH to reduce quinone, while pumping protons across the mitochondrial membrane. Detailed knowledge of the working principle of such coupled charge-transfer processes remains fragmentary due to bottlenecks arising from large conformational transitions and their interplay with the hydrated proton pathways. A recent study has reported the crystallographic structure of complex I from Thermus thermophilus, encasing 16 subunits with 9 iron-sulfur clusters, which are reduced by electrons from NADH. Here, we have used large-scale molecular dynamics simulations to study the chemo-mechanical coupling between redox changes of the iron-sulfur clusters and conformational transitions across complex I. First, we identify the redox switches within complex I, which couple the dynamics of the quinone binding pocket to the site of NADH reduction. Second, our free-energy calculations reveal that the affinity of the quinone, specifically menaquinone, for the binding-site is higher than that of its reduced, menaquinol form – a design essential for menaquinol release. Third, long-range hydrogen-bond networks connecting the quinone-binding site to the TM subunits are found to be responsible for proton pumping. Random insertion of molecular oxygen in reduced complex I illuminates an enhanced access to the iron-sulfur clusters, conducive to the formation of reactive oxygen species. Our simulations reveal molecular design principles linking redox reactions and proton translocation in complex I.