Free Energy Calculations Applied to Membrane Proteins

Selected applications of free energy calculations to the realm of membrane proteins are reviewed. The theoretical underpinnings of these calculations are described, focusing on free energy perturbation and the use of thermodynamic integration to determine free energy changes along well—delineated order parameters. Current strategies for improving the reliability of free energy calculations, while making them somewhat more affordable are outlined. Application of the free energy methodology to understand the structure and function of membrane proteins is illustrated in three concrete examples: The binding of an agonist ligand to a G protein—coupled receptor, the assisted transport of a small permeant through a membrane channel, and the recognition and association of transmembrane α—helical domains.