Computational Tools for Accurate Binding Free-Energy Prediction

A quantitative thermodynamic understanding of the noncovalent association of (bio)molecules is of central importance in molecular life sciences. An important quantity characterizing (bio)molecular association is the binding affinity or absolute binding free energy. In recent years, the computational prediction of absolute binding free energies has evolved considerably in terms of accuracy, computational speed, and user-friendliness. In this chapter, we first give an overview of how absolute free energies are defined and how they can be determined with computational means. We proceed with an outline of the theoretical basis of the two most reliable methods, potential of mean force, and double decoupling calculations. In particular, we describe how the sampling problem can be alleviated by application of restraints. Finally, we provide step-by-step instructions of how to set up corresponding molecular simulations with a commonly employed molecular dynamics simulation engine.