5
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      TIES 20: Relative Binding Free Energy with a Flexible Superimposition Algorithm and Partial Ring Morphing

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          The TIES (Thermodynamic Integration with Enhanced Sampling) protocol is a formally exact alchemical approach in computational chemistry to the calculation of relative binding free energies. The validity of TIES relies on the correctness of matching atoms across compared pairs of ligands, laying the foundation for the transformation along an alchemical pathway. We implement a flexible topology superimposition algorithm which uses an exhaustive joint-traversal for computing the largest common component(s). The algorithm is employed to enable matching and morphing of partial rings in the TIES protocol along with a validation study using 55 transformations and five different proteins from our previous work. We find that TIES 20 with the RESP charge system, using the new superimposition algorithm, reproduces the previous results with mean unsigned error of 0.75 kcal/mol with respect to the experimental data. Enabling the morphing of partial rings decreases the size of the alchemical region in the dual-topology transformations resulting in a significant improvement in the prediction precision. We find that increasing the ensemble size from 5 to 20 replicas per λ window only has a minimal impact on the accuracy. However, the non-normal nature of the relative free energy distributions underscores the importance of ensemble simulation. We further compare the results with the AM1-BCC charge system and show that it improves agreement with the experimental data by slightly over 10%. This improvement is partly due to AM1-BCC affecting only the charges of the atoms local to the mutation, which translates to even fewer morphed atoms, consequently reducing issues with sampling and therefore ensemble averaging. TIES 20, in conjunction with the enablement of ring morphing, reduces the size of the alchemical region and significantly improves the precision of the predicted free energies.

          Related collections

          Most cited references63

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          SciPy 1.0: fundamental algorithms for scientific computing in Python

          SciPy is an open-source scientific computing library for the Python programming language. Since its initial release in 2001, SciPy has become a de facto standard for leveraging scientific algorithms in Python, with over 600 unique code contributors, thousands of dependent packages, over 100,000 dependent repositories and millions of downloads per year. In this work, we provide an overview of the capabilities and development practices of SciPy 1.0 and highlight some recent technical developments.
            Bookmark
            • Record: found
            • Abstract: not found
            • Article: not found

            Matplotlib: A 2D Graphics Environment

              Bookmark
              • Record: found
              • Abstract: not found
              • Article: not found

              Comparison of simple potential functions for simulating liquid water

                Bookmark

                Author and article information

                Journal
                J Chem Theory Comput
                J Chem Theory Comput
                ct
                jctcce
                Journal of Chemical Theory and Computation
                American Chemical Society
                1549-9618
                1549-9626
                25 January 2021
                09 February 2021
                : 17
                : 2
                : 1250-1265
                Affiliations
                Centre for Computational Science, Department of Chemistry, University College London , 20 Gordon Street, London WC1H 0AJ, United Kingdom
                Author notes
                Article
                10.1021/acs.jctc.0c01179
                7876800
                33486956
                05a42970-60af-4f30-9b8e-4f0321057492
                © 2021 The Authors. Published by American Chemical Society

                This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.

                History
                : 10 November 2020
                Categories
                Article
                Custom metadata
                ct0c01179
                ct0c01179

                Computational chemistry & Modeling
                Computational chemistry & Modeling

                Comments

                Comment on this article