Membrane protein folding and stability: Physical principles

Stably folded membrane proteins reside in a free energy minimum determined by the interactions of the peptide chains with each other, the lipid bilaye r hydrocarbon core, the bilayer interface, and with water. The prediction o f three-dimensional structure from sequence requires a detailed understandi ng of these interactions. Progress toward this objective is summarized in t his review by means of a thermodynamic framework for describing membrane pr otein folding and stability. The framework includes a coherent thermodynami c formalism for determining and describing the energetics of peptide-bilaye r interactions and a review of the properties of the environment of membran e proteins-the bilayer milieu. Using a four-step thermodynamic cycle as a g uide, advances in three main aspects of membrane protein folding energetics are discussed: protein binding and folding in bilayer interfaces, transmem brane helix insertion, and helix-helix interactions. The concepts of membra ne protein stability that emerge provide insights to fundamental issues of protein folding.