Free Energy Calculations by the Molecular Mechanics Poisson−Boltzmann Surface Area Method

Abstract

Detailed knowledge of how molecules recognize interaction partners and of the conformational preferences of biomacromolecules is pivotal for understanding biochemical processes. Such knowledge also provides the foundation for the design of novel molecules, as undertaken in pharmaceutical research. Computer‐based free energy calculations enable a detailed investigation of the energetic factors that are responsible for molecular stability or binding affinity. The Molecular Mechanics Poisson–Boltzmann Surface Area (MM‐PBSA) approach is an efficient method for the calculation of free energies of diverse molecular systems. Here we describe the concepts of this approach and outline the practical proceeding. Furthermore we give an overview of the wide spectrum of problems that have been addressed with this method and of successful analyses carried out, thereby focussing on ambitious and recent studies. Limits of the approach in terms of accuracy and applicability are discussed. Despite these limitations MM‐PBSA is a method with great potential that allows comparative free energy analyses for various molecular systems at low computational cost.