Abstract

Complex I is a gigantic membrane-bound enzyme that transduces redox energy into a proton motive force across a biological membrane, powering cellular respiration. Despite major advances in recent years, its energy transduction principle remains unsolved and a major challenge. In this talk, I describe our integrative biophysical, computational, and structural approach to derive a molecular understanding of the long-range proton-pumping principles within the Complex I superfamily. Our findings reveal how the substrate reduction triggers conformational and hydration changes, how the protonation signal propagates across the membrane domain of the complex, and how engineering the elementary building blocks allows us to identify key mechanistic principles and probe effects underlying disease-related mutations. We suggest that Complex I employs electric field effects to control both catalysis and ion-transport, with striking physical similarities to other enzymes.