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Relative affinities of protein–cholesterol interactions from equilibrium molecular dynamics simulations
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Ansell, T. Bertie, Curran, Luke, Horrell, Michael R., Pipatpolkai, Tanadet, Letham, Suzanne C., Song, Wanling, Siebold, Christian, Stansfeld, Phillip J., Sansom, Mark S. P. and Corey, Robin A. (2021) Relative affinities of protein–cholesterol interactions from equilibrium molecular dynamics simulations. Journal of Chemical Theory and Computation, 17 (10). pp. 6548-6558. doi:10.1021/acs.jctc.1c00547 ISSN 1549-9626.
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WRAP-Relative-affinities-protein−cholesterol-interactions-equilibrium-dynamics-simulations-2021.pdf - Published Version - Requires a PDF viewer. Available under License Creative Commons Attribution 4.0. Download (3619Kb) | Preview |
Official URL: http://dx.doi.org/10.1021/acs.jctc.1c00547
Abstract
Specific interactions of lipids with membrane proteins contribute to protein stability and function. Multiple lipid interactions surrounding a membrane protein are often identified in molecular dynamics (MD) simulations and are, increasingly, resolved in cryo-electron microscopy (cryo-EM) densities. Determining the relative importance of specific interaction sites is aided by determination of lipid binding affinities using experimental or simulation methods. Here, we develop a method for determining protein–lipid binding affinities from equilibrium coarse-grained MD simulations using binding saturation curves, designed to mimic experimental protocols. We apply this method to directly obtain affinities for cholesterol binding to multiple sites on a range of membrane proteins and compare our results with free energies obtained from density-based equilibrium methods and with potential of mean force calculations, getting good agreement with respect to the ranking of affinities for different sites. Thus, our binding saturation method provides a robust, high-throughput alternative for determining the relative consequence of individual sites seen in, e.g., cryo-EM derived membrane protein structures surrounded by an array of ancillary lipid densities.
| Item Type: | Journal Article | |||||||||||||||||||||||||||||||||
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| Subjects: | Q Science > QP Physiology Q Science > QR Microbiology |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | |||||||||||||||||||||||||||||||||
| SWORD Depositor: | Library Publications Router | |||||||||||||||||||||||||||||||||
| Library of Congress Subject Headings (LCSH): | Lipids -- Metabolism, Membrane proteins , Molecular dynamics, Lipids -- Physiological transport, Membrane lipids, Protein binding | |||||||||||||||||||||||||||||||||
| Journal or Publication Title: | Journal of Chemical Theory and Computation | |||||||||||||||||||||||||||||||||
| Publisher: | American Chemical Society (ACS) | |||||||||||||||||||||||||||||||||
| ISSN: | 1549-9626 | |||||||||||||||||||||||||||||||||
| Official Date: | 12 October 2021 | |||||||||||||||||||||||||||||||||
| Dates: |
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| Volume: | 17 | |||||||||||||||||||||||||||||||||
| Number: | 10 | |||||||||||||||||||||||||||||||||
| Page Range: | pp. 6548-6558 | |||||||||||||||||||||||||||||||||
| DOI: | 10.1021/acs.jctc.1c00547 | |||||||||||||||||||||||||||||||||
| Status: | Peer Reviewed | |||||||||||||||||||||||||||||||||
| Publication Status: | Published | |||||||||||||||||||||||||||||||||
| Access rights to Published version: | Open Access (Creative Commons) | |||||||||||||||||||||||||||||||||
| Copyright Holders: | © 2021 The Authors. Published by American Chemical Society | |||||||||||||||||||||||||||||||||
| Date of first compliant deposit: | 24 September 2021 | |||||||||||||||||||||||||||||||||
| Date of first compliant Open Access: | 28 September 2021 | |||||||||||||||||||||||||||||||||
| RIOXX Funder/Project Grant: |
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