Chapter 4 Alchemical Free Energy Calculations: Ready for Prime Time?

Abstract

Publisher Summary In an alchemical transformation, a chemical species is transformed into another via a pathway of nonphysical (alchemical) states. Many physical processes, such as ligand binding or transfer of a molecule from gas to solvent, can be equivalently expressed as a composition of such alchemical transformations. Often, these alchemical processes are much more amenable to computational simulation than the physical process itself, especially in complex biochemical systems. A relative ligand-binding affinity, for example, may be computed via a thermodynamic cycle by alchemically transforming one ligand to another both bound to a receptor and in solution. There are other successful nonalchemical approaches for the computation of free energy differences, such as phase equilibrium Monte Carlo methods for modeling multicomponent fluids and potential of mean force methods. Alchemical approaches, however, generally allow for the larger range of conformational complexity typical of biochemical systems. This chapter discusses the efficiency and convergence of free energy methods rather than on accuracy, which is a function of the force field.