The role of intramolecular nonbonded interaction and angle sampling in single-step free energy perturbation
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AbstractSingle-step free energy perturbation (sFEP) has often been proposed as an efficient tool for a quick free energy scan due to its straightforward protocol and the ability to recycle an existing molecular dynamics trajectory for free energy calculations. Although sFEP is expected to fail when the sampling of a system is inefficient, it is often expected to hold for an alchemical transformation between ligands with a moderate difference in their sizes, e.g., transforming a benzene into an ethylbenzene. Yet, exceptions were observed in calculations for anisole and methylaniline, which have similar physical sizes as ethylbenzene. In this study, we show that such exceptions arise from the sampling inefficiency on an unexpected rigid degree of freedom, namely, the bond angle theta. The distributions of theta differ dramatically between two end states of a sFEP calculation, i.e., the conformation of the ligand changes significantly during the alchemical transformation process. Our investigation also reveals the interrelation between the ligand conformation and the intramolecular nonbonded interactions. This knowledge suggests a best combination of the ghost ligand potential and the dual topology setting, which improves the accuracy in a single reference sFEP calculation by bringing down its error from around 5k(B)T to k(B)T. Published by AIP Publishing.
All Author(s) ListChiang YC, Pang YT, Wang Y
Journal nameJournal of Chemical Physics
Detailed descriptionArticle Number: 234109
Volume Number145
Issue Number23
LanguagesEnglish-United Kingdom
Web of Science Subject CategoriesChemistry, Physical;Physics, Atomic, Molecular & Chemical;Chemistry;Physics

Last updated on 2021-22-09 at 01:01