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J Phys Chem B. 2019 Oct 24;123(42):8910-8915. doi: 10.1021/acs.jpcb.9b07593. Epub 2019 Oct 14.

Exploring the Effectiveness of Binding Free Energy Calculations.

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Department of Chemistry , University of Southern California , 418 SGM Building, 3620 McClintock Avenue , Los Angeles , California 90089-1062 , United States.
Department of Chemical Engineering , University of Michigan , 2300 Hayward Street , Ann Arbor , Michigan 48109 , United States.


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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