Recent theoretical and computational advances for modeling protein–ligand binding affinities

Abstract

We review recent theoretical and algorithmic advances for the modeling of protein ligand binding free energies. We first describe a statistical mechanics theory of noncovalent association, with particular focus on deriving the fundamental formulas on which computational methods are based. The second part reviews the main computational models and algorithms in current use or development, pointing out the relations with each other and with the theory developed in the first part. Particular emphasis is given to the modeling of conformational reorganization and entropic effect. The methods reviewed are free energy perturbation, double decoupling, the Binding Energy Distribution Analysis Method, the potential of mean force method, mining minima and MM/PBSA. These models have different features and limitations, and their ranges of applicability vary correspondingly. Yet their origins can all be traced back to a single fundamental theory.