BPS2026 – Rhodopsin as the hydrogen atom of lipid biophysics

Lipids are widely known as barriers to control the cellular environment and are important for preserving cell homeostasis. Recent lipidomics studies show the compositions of these membranes are highly diverse and affect physiological changes. Yet the basis of the molecular interactions which govern these physiological alterations are not well understood. Protein-lipid interactions have been traditionally explained by the fluid mosaic model which describes proteolipid coupling as weak and transient, with proteins diffusing freely in a passive lipid environment. However, considerable evidence shows there are out-of-plane-curvature forces indicated through the flexible surface model (FSM) that significantly impact protein function. Here, we use rhodopsin, a light sensitive G-protein-coupled receptor (GPCR), to explore protein dynamics. Rhodopsin is considered the hydrogen atom of membrane biophysics as it continues to be an excellent model system. We hypothesize that membrane biophysical properties influence protein conformational changes due to the lipidome. These properties include packing, elasticity, and asymmetry which are maintained through cell homeostasis. Upon photoactivation, rhodopsin adopts an equilibrium between the preactive metarhodopsin-I and active metarhodopsin-II state, providing a tool for monitoring protein conformational changes. We investigated compositional effects such as headgroup size, acyl chain length, and unsaturation which influence photoactivation of rhodopsin and discovered how membrane properties contribute to protein function. We show that smaller headgroups with longer acyl chains and higher degrees of unsaturation increase rhodopsin photoactivation as revealed by electronic spectroscopy and explained through an energy landscape model. 1 Collective biophysical properties of lipid membranes indicate that constant curvature stress (homeocurvature adaptation) is needed to regulate physiological processes. Understanding how protein function is shaped by its native environment and how cellular homeostasis governs curvatures stress provides new insight into how soft matter modulates biological mechanisms.