The Evolution of Lipids from Solvents to Substrates

While the role of water in soluble protein structure and function is well-established, the analogous role of lipids as a solvent for membrane proteins is less understood. Bacterial membranes exhibit extraordinary lipid diversity, with <i>Escherichia coli</i> synthesizing over 1,800 distinct glycerophospholipids. This lipid diversity gives rise to bulk membrane properties and specific lipid-lipid and lipid-protein interactions that directly affect α-IMP folding, assembly, and function. In this review, we use the same thermodynamic framework for understanding the solvation of soluble proteins to examine bacterial α-helical integral membrane protein (α-IMP) interactions with chemically diverse lipid environments. We propose that preferential solvent interactions were essential evolutionary drivers that enabled lipids to evolve as protein cofactors and substrates, with lipid chemical diversity creating unique evolutionary pressures distinct from those of aqueous systems.