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

Bieniek, MK; Bhati, AP; Wan, S; Coveney, PV; (2021) TIES 20: Relative Binding Free Energy with a Flexible Superimposition Algorithm and Partial Ring Morphing. Journal of Chemical Theory and Computation 10.1021/acs.jctc.0c01179. (In press). Green open access

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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.

Type: Article
Title: TIES 20: Relative Binding Free Energy with a Flexible Superimposition Algorithm and Partial Ring Morphing
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1021/acs.jctc.0c01179
Publisher version: http://dx.doi.org/10.1021/acs.jctc.0c01179
Language: English
Additional information: 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.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10120475
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