Free energy simulations to quantitatively study biomolecule stability and binding

Title: Free energy simulations to quantitatively study biomolecule stability and binding.

Authors: Sudarshan Behera, Carter J. Wilson, Lisa Schmidt, and Bert L. de Groot

Published in: Book chapter, Reference Module in Life Sciences, Elsevier (2025); preprint on ChemRxiv

Abstract: Free energy calculations based on molecular dynamics simulations offer a quantitative assessment of biomolecule binding and stability. This chapter discusses accurately estimating the free energy differences employing nonequilibrium alchemy. We cover the theoretical background, technical aspects of free energy simulations, and practical frameworks of efficient simulation set-up. The chapter also details several examples of large-scale quantitative estimations of binding free energy, including protein-ligand, protein-protein, and protein-nucleic acid binding. Overall, we provide a comprehensive guide to state-of-the-art simulation methods for accurate free energy calculations in the field of molecular biophysics and computational chemistry.