Please use this identifier to cite or link to this item:
http://bura.brunel.ac.uk/handle/2438/28479
Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Sahai, MA | - |
dc.contributor.author | Biggin, PC | - |
dc.date.accessioned | 2024-03-05T15:42:45Z | - |
dc.date.available | 2011-06-02 | - |
dc.date.available | 2024-03-05T15:42:45Z | - |
dc.date.issued | 2011-06-02 | - |
dc.identifier | ORCiD ID: M. A. Sahai https://orcid.org/0000-0002-2898-3112 | - |
dc.identifier | ORCiD ID: Philip Biggin https://orcid.org/0000-0001-5100-8836 | - |
dc.identifier.citation | Sahai, M.A. and Biggin, P.C. (2011). ‘Quantifying Water-Mediated Protein–Ligand Interactions in a Glutamate Receptor: A DFT Study’ in The Journal of Physical Chemistry B, Vol.115 (21)., pp. 7085 - 7096. DOI: https://doi.org/10.1021/jp200776t. | en_US |
dc.identifier.issn | 1520-6106 | - |
dc.identifier.uri | http://bura.brunel.ac.uk/handle/2438/28479 | - |
dc.description.abstract | It is becoming increasingly clear that careful treatment of water molecules in ligand-protein interactions is required in many cases if the correct binding pose is to be identified in molecular docking. Water can form complex bridging networks and can play a critical role in dictating the binding mode of ligands. A particularly striking example of this can be found in the ionotropic glutamate receptors. Despite possessing similar chemical moieties, crystal structures of glutamate and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) in complex with the ligand-binding core of the GluA2 ionotropic glutamate receptor revealed, contrary to all expectation, two distinct modes of binding. The difference appears to be related to the position of water molecules within the binding pocket. However, it is unclear exactly what governs the preference for water molecules to occupy a particular site in any one binding mode. In this work we use density functional theory (DFT) calculations to investigate the interaction energies and polarization effects of the various components of the binding pocket. Our results show (i) the energetics of a key water molecule are more favorable for the site found in the glutamate-bound mode compared to the alternative site observed in the AMPA-bound mode, (ii) polarization effects are important for glutamate but less so for AMPA, (iii) ligand-system interaction energies alone can predict the correct binding mode for glutamate, but for AMPA alternative modes of binding have similar interaction energies, and (iv) the internal energy is a significant factor for AMPA but not for glutamate. We discuss the results within the broader context of rational drug-design. © 2011 American Chemical Society. | en_US |
dc.description.sponsorship | Wellcome Trust and the Oxford Supercomputer Centre for support. M.A.S. thanks the Natural Sciences and Engineering Research Council of Canada, the Canadian Centennial Scholarship Fund and Hertford College for a Carreras Senior Scholarship. PCB is a Research Councils UK Fellow. | en_US |
dc.format.extent | 7085 - 7096 | - |
dc.publisher | American Chemical Society | en_US |
dc.rights | Copyright © 2011 American Chemical Society. This publication is licensed under these Terms of Use | - |
dc.rights.uri | http://pubs.acs.org/userimages/ContentEditor/1218220609981/authorchoice_form.pdf | - |
dc.rights.uri | https://pubs.acs.org/page/access-types | - |
dc.rights.uri | https://pubs.acs.org/page/rightslinkno.jsp | - |
dc.subject | Interaction energies | - |
dc.subject | Ligands | - |
dc.subject | Molecules | - |
dc.subject | Monomers | - |
dc.subject | Peptides and proteins | - |
dc.title | Quantifying water-mediated protein-ligand interactions in a glutamate receptor: A DFT study | en_US |
dc.type | Article | en_US |
dc.identifier.doi | http://dx.doi.org/10.1021/jp200776t | - |
dc.relation.isPartOf | Journal of Physical Chemistry B | - |
pubs.issue | 21 | - |
pubs.publication-status | Published | - |
pubs.volume | 115 | - |
dc.identifier.eissn | 1520-5207 | - |
Appears in Collections: | Dept of Life Sciences Research Papers |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
FullText.pdf | © 2011 American Chemical Society This is an open-access article distributed under the ACS Author Choice Terms & Conditions. Any use of this article, must conform to the terms of that license which are available at http://pubs.acs.org. | 7.47 MB | Adobe PDF | View/Open |
Items in BURA are protected by copyright, with all rights reserved, unless otherwise indicated.