Free-energy calculations

Abstract

Abstract The importance and challenge of calculating free energies using the statistical mechanical concepts developed in Chapters 1-7 are the topics in Chapter 8. The role of free energy calculations in problems such as drug-enzyme interactions, protein, and peptide conformational landscapes, chemical reaction profiles, and crystal polymorph ranking is highlighted. Techniques for computing free energies are discussed in detail and range from basic approach such as umbrella sampling, free energy perturbation, thermodynamic integration, and the bluemoon ensemble are presented. The challenge of treating rare events in free energy calculations is discussed together with the concepts of collective variables, reaction coordinates, and the need for targeted advanced sampling methods; these include metadynamics, the Jarzynski equality, Wang-Landau sampling, and driven adiabatic free energy dynamics. The chapter concludes with a discussion of the committor distribution as an ideal reaction coordinate and the use of the histogram test for collective variables considered as putative reaction coordinates