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Title: Molecular Dynamics Simulations Reveal the Conformational Flexibility of Lipid II and Its Loose Association with the Defensin Plectasin in the Staphylococcus aureus Membrane

Abstract

Lipid II is critical for peptidoglycan synthesis, which is the main component of the bacterial cell wall. Lipid II is a relatively conserved and important part of the cell wall biosynthesis pathway and is targeted by antibiotics such as the lantibiotics, which achieve their function by disrupting the biosynthesis of the cell wall. Given the urgent need for development of novel antibiotics to counter the growing threat of bacterial infection resistance, it is imperative that a thorough molecular-level characterization of the molecules targeted by antibiotics be achieved. To this end, we present here a molecular dynamics simulation study of the conformational dynamics of Lipid II within a detailed model of the Staphylococcus aureus cell membrane. We show that Lipid II is able to adopt a range of conformations, even within the packed lipidic environment of the membrane. Our simulations also reveal dimerization of Lipid II mediated by cations. In the presence of the defensin peptide plectasin, the conformational lability of Lipid II allows it to form loose complexes with the protein, via a number of different binding modes.

Authors:
 [1];  [2];  [3];  [4]
  1. Univ. of Southern Denmark, Odense (Denmark). Dept. of Physics, Chemistry and Pharmacy; Univ. of Southampton (United Kingdom). School of Chemistry
  2. Univ. of Southern Denmark, Odense (Denmark). Dept. of Physics, Chemistry and Pharmacy
  3. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Biosciences and Biotechnology Division
  4. Univ. of Southampton (United Kingdom). School of Chemistry
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1524722
Report Number(s):
LLNL-JRNL-679940
Journal ID: ISSN 0006-2960; 802879
Grant/Contract Number:  
AC52-07NA27344
Resource Type:
Accepted Manuscript
Journal Name:
Biochemistry
Additional Journal Information:
Journal Volume: 55; Journal Issue: 23; Journal ID: ISSN 0006-2960
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English

Citation Formats

Witzke, Sarah, Petersen, Michael, Carpenter, Timothy S., and Khalid, Syma. Molecular Dynamics Simulations Reveal the Conformational Flexibility of Lipid II and Its Loose Association with the Defensin Plectasin in the Staphylococcus aureus Membrane. United States: N. p., 2016. Web. doi:10.1021/acs.biochem.5b01315.
Witzke, Sarah, Petersen, Michael, Carpenter, Timothy S., & Khalid, Syma. Molecular Dynamics Simulations Reveal the Conformational Flexibility of Lipid II and Its Loose Association with the Defensin Plectasin in the Staphylococcus aureus Membrane. United States. doi:10.1021/acs.biochem.5b01315.
Witzke, Sarah, Petersen, Michael, Carpenter, Timothy S., and Khalid, Syma. Mon . "Molecular Dynamics Simulations Reveal the Conformational Flexibility of Lipid II and Its Loose Association with the Defensin Plectasin in the Staphylococcus aureus Membrane". United States. doi:10.1021/acs.biochem.5b01315. https://www.osti.gov/servlets/purl/1524722.
@article{osti_1524722,
title = {Molecular Dynamics Simulations Reveal the Conformational Flexibility of Lipid II and Its Loose Association with the Defensin Plectasin in the Staphylococcus aureus Membrane},
author = {Witzke, Sarah and Petersen, Michael and Carpenter, Timothy S. and Khalid, Syma},
abstractNote = {Lipid II is critical for peptidoglycan synthesis, which is the main component of the bacterial cell wall. Lipid II is a relatively conserved and important part of the cell wall biosynthesis pathway and is targeted by antibiotics such as the lantibiotics, which achieve their function by disrupting the biosynthesis of the cell wall. Given the urgent need for development of novel antibiotics to counter the growing threat of bacterial infection resistance, it is imperative that a thorough molecular-level characterization of the molecules targeted by antibiotics be achieved. To this end, we present here a molecular dynamics simulation study of the conformational dynamics of Lipid II within a detailed model of the Staphylococcus aureus cell membrane. We show that Lipid II is able to adopt a range of conformations, even within the packed lipidic environment of the membrane. Our simulations also reveal dimerization of Lipid II mediated by cations. In the presence of the defensin peptide plectasin, the conformational lability of Lipid II allows it to form loose complexes with the protein, via a number of different binding modes.},
doi = {10.1021/acs.biochem.5b01315},
journal = {Biochemistry},
number = 23,
volume = 55,
place = {United States},
year = {2016},
month = {5}
}

Journal Article:
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