Exploring ligand stability in protein crystal structures using binding pose metadynamics

Fusani, Lucia and Palmer, David S. and Somers, Donald O. and Wall, Ian D. (2020) Exploring ligand stability in protein crystal structures using binding pose metadynamics. Journal of Chemical Information and Modeling, 60 (3). pp. 1528-1539. ISSN 1549-9596 (https://doi.org/10.1021/acs.jcim.9b00843)

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Abstract

Identification of correct protein-ligand binding poses is important in structure-based drug design and crucial for the evaluation of protein-ligand binding affinity. Protein-ligand coordinates are commonly obtained from crystallography experiments that provide a static model of an ensemble of conformations. Binding pose metadynamics (BPMD) is an enhanced sampling method that allows for an efficient assessment of ligand stability in solution. Ligand poses that are unstable under the bias of the metadynamics simulation are expected to be infrequently occupied in the energy landscape, thus making minimal contributions to the binding affinity. Here, the robustness of the method is studied using crystal structures with ligands known to be incorrectly modeled, as well as 63 structurally diverse crystal structures with ligand fit to electron density from the Twilight database. Results show that BPMD can successfully differentiate compounds whose binding pose is not supported by the electron density from those with well-defined electron density.

ORCID iDs

Fusani, Lucia, Palmer, David S. ORCID logoORCID: https://orcid.org/0000-0003-4356-9144, Somers, Donald O. and Wall, Ian D.;
  • Item type:Article
    ID code:71146
    Dates:
    Date
    Event
    23 March 2020
    Published
    7 January 2020
    Published Online
    7 January 2020
    Accepted
    Notes:This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Chemical Information and Modeling, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jcim.9b00843.
    Subjects:Science > Chemistry
    Department:Faculty of Science > Pure and Applied Chemistry
    Depositing user: Pure Administrator
    Date deposited:21 Jan 2020 14:33
    Last modified:21 Nov 2024 01:17
    URI:https://strathprints.strath.ac.uk/id/eprint/71146
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