Significance
Complex I is a redox-driven proton pump, central for aerobic energy transduction. We show here by large-scale quantum and classical molecular simulations how reduction of quinone (Q) in the hydrophilic domain of complex I activates the proton pump in the membrane domain. Our simulations indicate that reduction of Q leads to local charge redistributions that trigger conformational changes via an array of alternating charged residues in the membrane domain, nearly 40 Å away. These mechanistic observations are supported by site-directed mutagenesis of a key residue triggering the activation process. The combined data provide molecular insight into how the long-range energy transduction is accomplished by complex I.</jats:p
