Charge-Changing Perturbations and Path Sampling via Classical Molecular Dynamic Simulations of Simple Guest–Host Systems

• Published in: Journal of chemical theory and computation Vol. 16; no. 12; pp. 7721 - 7734
• Main Authors: Öhlknecht, Christoph, Perthold, Jan Walther, Lier, Bettina, Oostenbrink, Chris
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 08.12.2020
• Subjects: Binding sites; Free energy; Fullerenes - chemistry; Ligands; Molecular dynamics; Molecular Dynamics Simulation; Perturbation; Proteins; Static Electricity; Thermodynamics
• ISSN: 1549-9618; 1549-9626
• DOI: 10.1021/acs.jctc.0c00719

Currently, two different methods dominate the field of biomolecular free-energy calculations for the prediction of binding affinities. Pathway methods are frequently used for large ligands that bind on the surface of a host, such as protein–protein complexes. Alchemical methods, on the other hand, are preferably applied for small ligands that bind to deeply buried binding sites. The latter methods are also widely known to be heavily artifacted by the representation of electrostatic energies in periodic simulation boxes, in particular, when net-charge changes are involved. Different methods have been described to deal with these artifacts, including postsimulation correction schemes and instantaneous correction schemes (e.g., co-alchemical perturbation of ions). Here, we use very simple test systems to show that instantaneous correction schemes with no change in the system net charge lower the artifacts but do not eliminate them. Furthermore, we show that free energies from pathway methods suffer from the same artifacts.