Retinal counterion switch mechanism in vision evaluated by molecular simulations

G protein-coupled receptors (GPCRs) comprise the largest protein family in the human genome,1 yet rhodopsin is the only member for which there is a high-resolution crystal structure.2 Understanding GPCR activation is significant due to its role in drug discovery and development. Of ca. 500 molecular sites for current drug therapy, cellular membrane receptors are the largest subgroup and represent 45 % of all targets.3 Here we show how analysis of the rhodopsin chromophore retinal by molecular dynamics (MD) simulations with experimental 2H NMR data gives insights into the counterion switch mechanism that stabilizes the protonated Schiff base (PSB). Disruption of the retinal PSB is thermodynami-cally the most important event that characterizes the activated metarhodopsin II (MII) state.4 Current advances in supercomputing5 have made it possible to extend MD simulations to the unprecedented time scales describe