Rhodopsin, the primary dim light receptor and the only G-protein coupled receptor with known atomic structure, is found in the rod outer disk membranes in the retina. These membranes have a unique composition, highly enriched in polyunsaturated ��-3 lipid chains and cholesterol. This composition modulates rhodopsin's activity: ��-3 fatty acids such as DHA enhance the kinetics of the photocycle and shift the equilibrium toward the active Meta-II state, while cholesterol has the opposite effect, slowing the photocycle and stabilizing the native state. The systematic manner in which the cell regulates the lipid species suggests two questions: How do cholesterol and polyunsaturated chains affect rhodopsin? What physical phenomena drive these interactions?

To answer these questions, we performed a series of molecular dynamics simulations of rhodopsin in a membrane containing two polyunsaturated lipid species and cholesterol. Our results indicate that polyunsaturated chains and cholesterol modulate rhodopsin via totally different mechanisms: the protein surface is preferentially solvated by DHA, while cholesterol is largely excluded from the protein surface. We conclude that cholesterol acts on the protein indirectly, by relieving the intramembrane strain induced by rhodopsin's hourglass shape. By contrast, we found evidence for specific, localized binding sites for DHA on the protein surface; the presence of bound DHA chains was correlated with weakened interhelical contacts, suggesting that DHA speeds the photocycle by destabilizing the native state.