Bacteriorhodopsin proton-pumping mechanism: Successes and challenges in computational approaches

Bacteriorhodopsin (bR) is perhaps the best-studied proton pump. Over about four decades, research on this fascinating photocyclic light-driven protein inspired the development of key experimental and computational methodologies that are now widely used in membrane protein studies. We review here failures and successes in computational approaches that have been applied to study the bR proton-transfer steps. Conflict between experimental results pertaining to the proton transfer mechanisms in the early photocycle intermediates was resolved by detailed quantum mechanical/molecular mechanical computation, the results of which were confirmed more than a decade later. Key to this approach was the realization that, to understand how the pump works and achieves directional transfer of protons, the individual reaction steps-proton transfer and reorganization of the internal hydrogen-bond network-needed to be considered within the context of the energy landscape of the complete reaction cycle.