The central theme of the talk is how small-scale chemical reactions, which involve the making and breaking of chemical bonds, are coupled to large conformational changes that are linked to the biological functions of proteins. As a prime example, we will discuss ATP-binding cassette (ABC) transporters, a class of membrane proteins that translocate substrate molecules across biological membranes by chemomechanically coupling ATP binding and hydrolysis in the nucleotide-binding domains to large-scale conformational changes of the transmembrane domains. Despite recent progress in the determination of high-resolution structures of substrate-bound ABC exporters, the inherently dynamic mechanism of substrate transport remained unclear at the atomic level. We combined atomistic molecular dynamics (MD) simulations and hybrid quantum mechanics/molecular mechanics (QM/MM) simulations to reveal the atomic-level mechanisms of how the ATP-related “power stroke” ultimately leads to the conformational changes of the transporter that drive substrate translocation across the membrane. Analogies to the chemomechanics of other ATP-powered biomolecular machines will be discussed.
