Resolving Chemical Dynamics in Biological Energy Conversion: Long-Range Proton-Coupled Electron Transfer in Respiratory Complex I

[Image: see text] Biological energy conversion is catalyzed by membrane-bound proteins that transduce chemical or light energy into energy forms that power endergonic processes in the cell. At a molecular level, these catalytic processes involve elementary electron-, proton-, charge-, and energy-transfer reactions that take place in the intricate molecular machineries of cell respiration and photosynthesis. Recent developments in structural biology, particularly cryo-electron microscopy (cryoEM), have resolved the molecular architecture of several energy transducing proteins, but detailed mechanistic principles of their charge transfer reactions still remain poorly understood and a major challenge for modern biochemical research. To this end, multiscale molecular simulations provide a powerful approach to probe mechanistic principles on a broad range of time scales (femtoseconds to milliseconds) and spatial resolutions (10(1)–10(6) atoms), although technical challenges also require balancing between the computational accuracy, cost, and approximations introduced within the model. Here we discuss how the combination of atomistic (aMD) and hybrid quantum/classical molecular dynamics (QM/MM MD) simulations with free energy (FE) sampling methods can be used to probe mechanistic principles of enzymes responsible for biological energy conversion. We present mechanistic explorations of long-range proton-coupled electron transfer (PCET) dynamics in the highly intricate respiratory chain enzyme Complex I, which functions as a redox-driven proton pump in bacterial and mitochondrial respiratory chains by catalyzing a 300 Å fully reversible PCET process. This process is initiated by a hydride (H(–)) transfer between NADH and FMN, followed by long-range (>100 Å) electron transfer along a wire of 8 FeS centers leading to a quinone biding site. The reduction of the quinone to quinol initiates dissociation of the latter to a second membrane-bound binding site, and triggers proton pumping across the membrane domain of complex I, in subunits up to 200 Å away from the active site. Our simulations across different size and time scales suggest that transient charge transfer reactions lead to changes in the internal hydration state of key regions, local electric fields, and the conformation of conserved ion pairs, which in turn modulate the dynamics of functional steps along the reaction cycle. Similar functional principles, which operate on much shorter length scales, are also found in some unrelated proteins, suggesting that enzymes may employ conserved principles in the catalysis of biological energy transduction processes.