Rhodopsin: The hydrogen atom of membrane biophysics

Membranes possess characteristic lipidomes that are preserved by homeostatic regulation, even as environmental conditions change. Technological advancements in lipidomics instrumentation have revealed that altering this composition can produce significant physiological effects and can influence protein function. As lipidomics has expanded our view of membrane diversity, a key question remains: which membrane features must be maintained by cells to ensure proper protein function? Here, we focus on key membrane properties such as asymmetry, packing, and elasticity and highlight cases in which lipid composition modulates protein function. We find that curvature stress is a likely target of such regulation and accounts for the gradual changes in protein activity observed across lipid series that differ systematically in their physical properties. Curvature stress arises when there is a difference between the actual (mean) and preferred (spontaneous) curvature of a membrane. The magnitude of the stress depends on the amount of deformation and the membrane bending rigidity, both of which depend on lipid packing. These properties are further modulated by composition and number asymmetry between the two leaflets. Throughout these studies, rhodopsin has played a pivotal role in uncovering these principles due to its natural abundance and spectroscopic accessibility, enabling experiments that would be difficult or impossible with other membrane proteins. We therefore consider rhodopsin as the hydrogen atom of membrane biophysics in recognition of its unparalleled significance as a model system, in analogy to how the hydrogen atom provides the foundation for atomic theory. Because rhodopsin uniquely permits precise measurements of conformational equilibria, it remains a powerful system for dissecting how lipid composition and asymmetry give rise to membrane curvature adaptation.