G-protein coupled receptors (GPCR) comprise the largest class of enzymes in humans. They serve as major targets for small-molecule pharmaceuticals and as platforms for fundamental studies of signal transduction. Rhodopsin is a prototypical GPCR responsible for dim-light photoreception. Its activation involves photoisomerization of the 11-<i>cis</i>-retinyl chromophore into the all-trans form, followed by hydrolysis of the Schiff-base linkage that binds the chromophore the protein. Competing thermal processes, including thermal isomerization and hydrolysis, could limit the sensitivity of the system to dim light. Remarkably, however, rhodopsin has evolved to have robust thermal stability (decay time ~430 years). The origin of such an impressive stability remains to be understood at the molecular level.<br/>We provide an atomistic account of thermal decay rates in bovine rhodopsin via a quantum-mechanics/molecular mechanics (QM/MM) analysis of the underlying decay mechanisms. We study the functional role of bound water molecules during hydrolysis of the protonated Schiff base linkage, and the effect of single point mutations on the hydrogen-bond network of the extracellular loop II that maintains thermal stability. Our QM/MM description is partially validated by direct comparisons to mutagenesis studies combined with experimental measurements of thermal decay rates.

QM/MM studies of rhodopsin thermal decay

251st National Meeting (2016)

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