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Membrane binding of antimicrobial peptides is modulated by lipid charge modification
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Simcock, Patrick W., Bublitz, Maike, Cipcigan, Flaviu, Ryadnov, Maxim G., Crain, Jason, Stansfeld, Phillip J. and Sansom, Mark S. P. (2021) Membrane binding of antimicrobial peptides is modulated by lipid charge modification. Journal of Chemical Theory and Computation, 17 (2). pp. 1218-1228. doi:10.1021/acs.jctc.0c01025 ISSN 1549-9618.
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WRAP-membrane-binding-antimicrobial-peptides-modulated-lipid-charge-modification-Stansfeld-2021.pdf - Accepted Version - Requires a PDF viewer. Download (1937Kb) | Preview |
Official URL: http://dx.doi.org/10.1021/acs.jctc.0c01025
Abstract
Peptide interactions with lipid bilayers play a key role in a range of biological processes and depend on electrostatic interactions between charged amino acids and lipid headgroups. Antimicrobial peptides (AMPs) initiate the killing of bacteria by binding to and destabilizing their membranes. The multiple peptide resistance factor (MprF) provides a defense mechanism for bacteria against a broad range of AMPs. MprF reduces the negative charge of bacterial membranes through enzymatic conversion of the anionic lipid phosphatidyl glycerol (PG) to either zwitterionic alanyl-phosphatidyl glycerol (Ala-PG) or cationic lysyl-phosphatidyl glycerol (Lys-PG). The resulting change in the membrane charge is suggested to reduce the binding of AMPs to membranes, thus impeding downstream AMP activity. Using coarse-grained molecular dynamics to investigate the effects of these modified lipids on AMP binding to model membranes, we show that AMPs have substantially reduced affinity for model membranes containing Ala-PG or Lys-PG. More than 5000 simulations in total are used to define the relationship between lipid bilayer composition, peptide sequence (using five different membrane-active peptides), and peptide binding to membranes. The degree of interaction of a peptide with a membrane correlates with the membrane surface charge density. Free energy profile (potential of mean force) calculations reveal that the lipid modifications due to MprF alter the energy barrier to peptide helix penetration of the bilayer. These results will offer a guide to the design of novel peptides, which addresses the issue of resistance via MprF-mediated membrane modification.
| Item Type: | Journal Article | |||||||||||||||||||||||||||
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| Subjects: | Q Science > QP Physiology R Medicine > RS Pharmacy and materia medica |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) Faculty of Science, Engineering and Medicine > Science > Chemistry > Computational and Theoretical Chemistry Centre |
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| Library of Congress Subject Headings (LCSH): | Peptide antibiotics , Molecular dynamics -- Simulation methods, Membrane lipids | |||||||||||||||||||||||||||
| Journal or Publication Title: | Journal of Chemical Theory and Computation | |||||||||||||||||||||||||||
| Publisher: | American Chemical Society | |||||||||||||||||||||||||||
| ISSN: | 1549-9618 | |||||||||||||||||||||||||||
| Official Date: | 9 February 2021 | |||||||||||||||||||||||||||
| Dates: |
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| Volume: | 17 | |||||||||||||||||||||||||||
| Number: | 2 | |||||||||||||||||||||||||||
| Page Range: | pp. 1218-1228 | |||||||||||||||||||||||||||
| DOI: | 10.1021/acs.jctc.0c01025 | |||||||||||||||||||||||||||
| Status: | Peer Reviewed | |||||||||||||||||||||||||||
| Publication Status: | Published | |||||||||||||||||||||||||||
| Reuse Statement (publisher, data, author rights): | This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Chemical Theory and Computation, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/acs.jctc.0c01025 | |||||||||||||||||||||||||||
| Access rights to Published version: | Restricted or Subscription Access | |||||||||||||||||||||||||||
| Date of first compliant deposit: | 18 February 2021 | |||||||||||||||||||||||||||
| Date of first compliant Open Access: | 4 January 2022 | |||||||||||||||||||||||||||
| RIOXX Funder/Project Grant: |
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