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

Abstract

Conspectus 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.

Molecular Principles of Redox-Coupled Protonation Dynamics in Photosystem II

“…In addition to PSII, other bioenergetically relevant protein complexes may also employ similar redox-driven protonation steps via conformational changes in conserved buried ion-pairs, electrostatically modulating the reaction barriers for the catalytic steps. 47 , 58 Such conformational changes in ion-pairs could be responsible for long-range proton transport within the membrane domain of respiratory complex I, 59 − 61 a gigantic redox-driven proton pump that initiates cell respiration in the mitochondria. 58 , 62 Similar effects are also found in cytochrome c oxidase, where redox-driven dissociation of a propionate-arginine (Δ-propionate/Arg438 in bovine numbering) ion-pair modulates the proton transfer barriers across the membrane.…”

“…To probe the light-driven water oxidation mechanism in PSII, we develop here a multi-scale molecular simulation approach, 47 where we combine quantum chemical density functional theory (DFT) and hybrid quantum/classical (QM/MM) calculations to study the energetics and dynamics of the bond-breaking/bond-formation processes, with classical atomistic molecular dynamics (MD) simulations, which allows us to sample the large-scale dynamics of PSII on microsecond timescales in a biological membrane-water environment ( Figure 1 and Figure S1 ). To gain insight into the protonation dynamics, we focus here on the S 2 Y z → S 3 Y z and S 3 Y z → S 4 /S 0 Y z transitions that couple to the oxidation and deprotonation of the substrate water molecule and formation of the O–O bond.…”

The clinically relevant triple mutation in the mtND1 gene inactivates Escherichia coli complex I

“…Energy-converting NADH:ubiquinone oxidoreductase, respiratory complex I, is the main entry point for electrons from NADH into many respiratory chains. Complex I couples the transfer of two electrons from NADH to a quinone (Q) with the translocation of four protons across the membrane [1][2][3][4][5][6]. It has a twopart structure consisting of a peripheral arm catalysing electron transfer and a membrane arm executing proton translocation [6][7][8][9][10].…”

“…It has a twopart structure consisting of a peripheral arm catalysing electron transfer and a membrane arm executing proton translocation [6][7][8][9][10]. The mitochondrial complex of mammals consists of 45 subunits including the 14 conserved core subunits that are found in all species containing an energy-converting NADH:Q oxidoreductase [1][2][3][4][5][6]11]. Seven of the 14 core subunits are encoded by mitochondrial DNA (mtDNA) in humans [1,11].…”

“…It turned out that the single variant is stably assembled and showed a decreased electron transfer activity that was fully coupled to proton translocation. Remarkably, this variant exhibits significant activation kinetics, which was interpreted as a disturbed Q chemistry [2,25,[34][35][36]. Various amino acid residues are found in positions L200 (e.g.…”