Not just an oil slick: how the energetics of protein-membrane interactions impacts the function and organization of transmembrane proteins.

The membrane environment, its composition, dynamics, and remodeling, have been shown to participate in the function and organization of a wide variety of transmembrane (TM) proteins, making it necessary to study the molecular mechanisms of such proteins in the context of their membrane settings. We review some recent conceptual advances enabling such studies, and corresponding computational models and tools designed to facilitate the concerted experimental and computational investigation of protein-membrane interactions. To connect productively with the high resolution achieved by cognate experimental approaches, the computational methods must offer quantitative data at an atomistically detailed level. We show how such a quantitative method illuminated the mechanistic importance of a structural characteristic of multihelical TM proteins, that is, the likely presence of adjacent polar and hydrophobic residues at the protein-membrane interface. Such adjacency can preclude the complete alleviation of the well-known hydrophobic mismatch between TM proteins and the surrounding membrane, giving rise to an energy cost of residual hydrophobic mismatch. The energy cost and biophysical formulation of hydrophobic mismatch and residual hydrophobic mismatch are reviewed in the context of their mechanistic role in the function of prototypical members of multihelical TM protein families: 1), LeuT, a bacterial homolog of mammalian neurotransmitter sodium symporters; and 2), rhodopsin and the β1- and β2-adrenergic receptors from the G-protein coupled receptor family. The type of computational analysis provided by these examples is poised to translate the rapidly growing structural data for the many TM protein families that are of great importance to cell function into ever more incisive insights into mechanisms driven by protein-ligand and protein-protein interactions in the membrane environment.