Journal
JOURNAL OF PHYSICAL CHEMISTRY B
Volume 123, Issue 42, Pages 8910-8915Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jpcb.9b07593
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Funding
- NIH [R35GM-122472]
- NSF REU [CHE 1757942]
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Increasing the accuracy of the evaluation of ligand-binding energies is one of the most important tasks of current computational biology. Here we explore the accuracy of free energy perturbation (FEP) approaches by comparing the performance of a regular FEP method to the one using replica exchange to enhance the sampling on a well-defined benchmark. The examination was limited to the so-called alchemical perturbations which are restricted to a fragment of the drug, and therefore, the calculation is a relative one rather than the absolute binding energy of the drug. Overall, our calculations reach the 1 kcal/mol accuracy limit. It is also shown that the accurate prediction of the position of water molecules around the binding pocket is important for FEP calculations. Interestingly, the replica exchange method does not significantly improve the accuracy of binding energies, suggesting that we reach the limit where the force field quality is a critical factor for accurate calculations.
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