Darby, John Fintan orcid.org/0000-0003-2754-6348, Hopkins, Adam, Hubbard, Roderick Eliot orcid.org/0000-0002-8233-7461 et al. (6 more authors) (2019) Water networks can determine the affinity of ligand binding to proteins. Journal of the American Chemical Society. pp. 15818-15826. ISSN 1520-5126
Abstract
Solvent organization is a key but underexploited contributor to the thermodynamics of protein–ligand recognition, with implications for ligand discovery, drug resistance and protein engineering. Here, we explore the contribution of solvent to ligand binding in the Haemophilus influenzae virulence protein SiaP. By introducing a single mutation without direct ligand contacts, we observed a >1000-fold change in sialic acid binding affinity. Crystallographic and calorimetric data of wild-type and mutant SiaP showed that this change results from an enthalpically unfavourable perturbation of the solvent network. This disruption is reflected by changes in the normalized atomic displacement parameters of crystallographic water molecules. In SiaP’s enclosed cavity, relative differences in water-network dynamics serve as a simple predictor of changes in the free energy of binding upon changing protein, ligand or both. This suggests that solvent structure is an evolutionary con-straint on protein sequence that contributes to ligand affinity and selectivity.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details. |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Chemistry (York) The University of York > Faculty of Sciences (York) > Centre for Immunology and Infection (CII) (York) The University of York > Faculty of Sciences (York) > Biology (York) |
Depositing User: | Pure (York) |
Date Deposited: | 25 Sep 2019 08:10 |
Last Modified: | 06 Dec 2024 00:16 |
Published Version: | https://doi.org/10.1021/jacs.9b06275 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1021/jacs.9b06275 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:151301 |
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