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      Using AMBER18 for Relative Free Energy Calculations

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      Journal of Chemical Information and Modeling
      American Chemical Society (ACS)

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          Abstract

          With renewed interest in free energy methods in contemporary structure-based drug design there is a pressing need to validate against multiple targets and force fields to assess the overall ability of these methods to accurately predict relative binding free energies. We computed relative binding free energies using GPU accelerated Thermodynamic Integration (GPU-TI) on a dataset originally assembled by Schrödinger, Inc.. Using their GPU free energy code (FEP+) and the OPLS2.1 force field combined with the REST2 enhanced sampling approach, these authors obtained an overall MUE of 0.9 kcal/mol and an overall RMSD of 1.14 kcal/mol. In our study using GPU-TI from AMBER with the AMBER14SB/GAFF1.8 force field but without enhanced sampling, we obtained an overall MUE of 1.17 kcal/mol and an overall RMSD of 1.50 kcal/mol for the 330 perturbations contained in this data set. A more detailed analyses of our results suggested that the observed differences between the two studies arise from differences in sampling protocols along with differences in the force fields employed. Future work should address the problem of establishing benchmark quality results with robust statistical error bars obtained through multiple independent runs and enhanced sampling, which is possible with the GPU-accelerated features in AMBER.

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          Author and article information

          Journal
          Journal of Chemical Information and Modeling
          J. Chem. Inf. Model.
          American Chemical Society (ACS)
          1549-9596
          1549-960X
          June 06 2019
          June 06 2019
          Article
          10.1021/acs.jcim.9b00105
          7371000
          31244091
          5eee9b63-bf0a-43f5-a965-113aabeed47c
          © 2019
          History

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