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The aerobic electron transfer chain builds a proton gradient by proton coupled electron transfer reactions through a series of proteins. Complex I is the 昀椀rst enzyme in the sequence. Here transfer of two electrons from NADH to quinone yields four protons pumped from the membrane N- (negative, higher pH) side to the P- (positive, lower pH) side. Protons move through three linear antiporter paths, with a few amino acids and waters providing the route; and through the E-channel, a complex of competing paths, with clusters of interconnected protonatable residues. Proton loading sites (PLS) transiently bind protons as they are transported from N- to P-compartments. PLS can be individual residues or extended clusters of residues. The program MCCE uses Monte Carlos sampling to analyze the E-channel proton binding in equilibrium with individual Molecular Dynamics snapshots from tra- jectories of Thermus thermuphillus Complex I in the apo, quinone and quinol bound states. At pH 7, the 昀椀ve E- channel subunits (Nqo4, Nqo7, Nqo8, Nqo10, and Nqo11) take >25,000 protonation microstates, each with different residues protonated. The microstate explosion is tamed by analyzing interconnected clusters of residues along the proton transfer paths. A proton is bound and released from a cluster of 昀椀ve coupled residues on the protein N-side and to six coupled residues in the protein center. Loaded microstates bind protons to sites closer to the P-side in the forward pumping direction. MCCE microstate analysis identi昀椀es strongly coupled proton binding amongst individual residues in the two PLS clusters.more » « lessFree, publicly-accessible full text available January 1, 2026
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null (Ed.)• Water is the primary cellular solvent, yet is challenging to simulate computationally. Here we simulate water molecules in the Gramicidin A channel comparing Monte Carlo (MC) sampling with a continuum electrostatics and Molecular Dynamics (MD) calculations with the non-polarizable CHARMM36 and polarizable Drude force fields. • These give different water properties, with classical MD yielding well oriented water wires, while the Drude or continuum electrostatics force fields lead to more disordered water molecules, often changing orientation in the middle of the channel.more » « less