Energetics of membrane protein folding and stability

The critical role of membrane proteins in a myriad of biological and physiological functions has spawned numerous investigations over the past several decades with the long-term goal of identifying the molecular origins and energetic forces that stabilize these proteins within the membrane. Parallel structural and thermodynamics studies on several systems have provided significant insight regarding the driving forces governing folding, assembly, insertion, and translocation of membrane proteins. The present review surveys families of membrane-associated proteins including α-helical and β-barrel structures, viral surface receptors, and pore-forming toxins, citing representative proteins within each of these classes for further scrutiny in terms of structure–function relationships and global conformational stability. This overview presents seminal findings from pioneering studies on the energetics of membrane protein folding and stability to modern techniques that are exploiting the use of molecular genetics and single molecule studies. An overall consensus regarding the molecular origins of membrane protein stability is that a number of intrinsic properties resemble features of soluble proteins, yet there are distinct energetic differences arising from specific intra- and intermolecular interactions within the membrane. The combined efforts from structural, energetics, and dynamics approaches offer unique insights and improve our fundamental understanding of the driving forces dictating membrane protein folding and stability.