Challenges Encountered Applying Equilibrium and Nonequilibrium Binding Free Energy Calculations

• DOI: 10.1021/acs.jpcb.0c10263
• Publication Date: 2021-04-28T01:34:20Z
• Authors: Hannah M. Baumann; Vytautas Gapsys; Bert L. de Groot; David L. Mobley
• Keywords: 0301 basic medicine; 570; Entropy; Proteins; 02 engineering and technology; Molecular Dynamics Simulation; Ligands; 01 natural sciences; Physical sciences; Medicinal and Biomolecular Chemistry; 03 medical and health sciences; Engineering; Chemical sciences; Chemical Sciences; Physical Sciences; 0103 physical sciences; Thermodynamics; Generic health relevance; 0210 nano-technology; Protein Binding

Binding free energy calculations have become increasingly valuable to drive decision making in drug discovery projects. However, among other issues, inadequate sampling can reduce accuracy, limiting the value of the technique.In this paper we apply absolute binding free energy calculations to ligands binding to T4 lysozyme L99A and HSP90 using equilibrium and non-equilibrium approaches. We highlight sampling problems encountered in these systems, such as slow side chain rearrangements and slow changes of water placement upon ligand binding. These same types of challenges are likely to show up in other protein-ligand systems as well and we propose some strategies to diagnose and test for such problems in alchemical free energy calculations. We also explore similarities and differences in how the equilibrium and the non-equilibrium approaches handle these problems. Our results show the large amount of work still to be done to make free energy calculations robust and reliable and provide insight for future research in this area.