Chapter 3: Free Energy Calculations for Understanding Membrane Receptors

Free energy is probably the single, most informative quantity that can be obtained from atomistic computer simulations of chemical and biological systems. In this chapter, the basic methods that have been most frequently applied to calculating free energy differences between different states of membrane receptors are outlined. These methods are based on free energy perturbation theory, probability density approaches, and thermodynamic integration. The emphases are on the conceptual connection between different methods and on “good practices” in their applications. A number of techniques, including replica exchange, can be used to enhance sampling of the relevant regions of the configurational space and, by doing so, improve the reliability of calculated free energies. Several illustrative examples in which free energy calculations have been applied to improve our understanding of membrane receptors are presented. They involve binding of anesthetic ligands to receptors, transitions between inactive and active states of receptors, and estimating the ionic conductance from the free energy profile of ions along a channel. They were selected in part to demonstrate the diversity of approaches that can be brought to bear to study membrane receptors computationally.