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

Journal Article · · Biochemistry
 [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
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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.

Research Organization:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Organization:
USDOE
Grant/Contract Number:
AC52-07NA27344
OSTI ID:
1524722
Report Number(s):
LLNL-JRNL--679940; 802879
Journal Information:
Biochemistry, Journal Name: Biochemistry Journal Issue: 23 Vol. 55; ISSN 0006-2960
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
English

References (48)

Scalable molecular dynamics with NAMD journal January 2005
Additive empirical force field for hexopyranose monosaccharides journal November 2008
CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields journal January 2009
CHARMM-GUI Membrane Builder toward realistic biological membrane simulations journal August 2014
Racemic crystallography of synthetic protein enantiomers used to determine the X-ray structure of plectasin by direct methods journal June 2009
CHAMBER: Comprehensive support for CHARMM force fields within the AMBER software journal December 2009
Changes in permeability of Staphylococcus aureus and derived liposomes with varying lipid composition journal March 1972
Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes journal March 1977
VMD: Visual molecular dynamics journal February 1996
Bacterial resistance to vancomycin: five genes and one missing hydrogen bond tell the story journal January 1996
The Effect of Environment on the Recognition and Binding of Vancomycin to Native and Resistant Forms of Lipid II journal December 2011
Correction journal January 2013
An oldie but a goodie – cell wall biosynthesis as antibiotic target pathway journal February 2010
Lipid II: A central component in bacterial cell wall synthesis and a target for antibiotics journal September 2008
Mapping the Targeted Membrane Pore Formation Mechanism by Solution NMR:  The Nisin Z and Lipid II Interaction in SDS Micelles journal June 2002
Assembly and Stability of Nisin−Lipid II Pores † journal September 2004
PROPKA3: Consistent Treatment of Internal and Surface Residues in Empirical p K a Predictions journal December 2010
Improved Treatment of Ligands and Coupling Effects in Empirical Calculation and Rationalization of p K a Values journal June 2011
CHARMM Additive All-Atom Force Field for Carbohydrate Derivatives and Its Utility in Polysaccharide and Carbohydrate–Protein Modeling journal August 2011
Optimization of the Additive CHARMM All-Atom Protein Force Field Targeting Improved Sampling of the Backbone ϕ, ψ and Side-Chain χ 1 and χ 2 Dihedral Angles journal August 2012
PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data journal June 2013
CHARMM Additive All-Atom Force Field for Glycosidic Linkages between Hexopyranoses journal August 2009
Improved Treatment of the Protein Backbone in Empirical Force Fields journal January 2004
Update of the CHARMM All-Atom Additive Force Field for Lipids: Validation on Six Lipid Types journal June 2010
Influence of Solvent and Intramolecular Hydrogen Bonding on the Conformational Properties of O-Linked Glycopeptides journal September 2011
Electroporation of the E. coli and S. Aureus Membranes: Molecular Dynamics Simulations of Complex Bacterial Membranes journal November 2011
All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins † journal April 1998
Plectasin is a peptide antibiotic with therapeutic potential from a saprophytic fungus journal October 2005
A new antibiotic kills pathogens without detectable resistance journal January 2015
Lipid II as a target for antibiotics journal March 2006
The nisin–lipid II complex reveals a pyrophosphate cage that provides a blueprint for novel antibiotics journal September 2004
Lipid-II forms potential “landing terrain” for lantibiotics in simulated bacterial membrane journal April 2013
Comparison of simple potential functions for simulating liquid water journal July 1983
Molecular dynamics with coupling to an external bath journal October 1984
Particle mesh Ewald: An N ⋅log( N ) method for Ewald sums in large systems journal June 1993
Finite representation of an infinite bulk system: Solvent boundary potential for computer simulations journal June 1994
Constant pressure molecular dynamics algorithms journal September 1994
Constant pressure molecular dynamics simulation: The Langevin piston method journal September 1995
Crystal structure of Staphylococcus aureus transglycosylase in complex with a lipid II analog and elucidation of peptidoglycan synthesis mechanism journal April 2012
An analysis of the accuracy of Langevin and molecular dynamics algorithms journal December 1988
In vitro assembly of a complete, pentaglycine interpeptide bridge containing cell wall precursor (lipid II-Gly5) of Staphylococcus aureus: S. aureus in vitro interpeptide bridge synthesis journal June 2004
Plectasin, a Fungal Defensin, Targets the Bacterial Cell Wall Precursor Lipid II journal May 2010
Plectasin Shows Intracellular Activity against Staphylococcus aureus in Human THP-1 Monocytes and in a Mouse Peritonitis Model journal November 2009
Metabolism of Phosphatidylglycerol and Lysyl Phosphatidylglycerol in Staphylococcus aureus journal December 1970
Fatty Acid Composition of the Complex Lipids of Staphylococcus aureus During the Formation of the Membrane-bound Electron Transport System journal June 1968
Lipid Intermediates in the Biosynthesis of Bacterial Peptidoglycan journal December 2007
Metabolism of Phosphatidylglycerol and Lysyl Phosphatidylglycerol in Staphylococcus aureus journal December 1970
Fatty Acid Composition of the Complex Lipids of Staphylococcus aureus During the Formation of the Membrane-bound Electron Transport System journal June 1968

Cited By (2)

The role of the jaw subdomain of peptidoglycan glycosyltransferases for lipid II polymerization journal June 2018
Flotillin mediated membrane fluidity controls peptidoglycan synthesis and MreB movement posted_content April 2019

Figures / Tables (15)

Figure 1(p. 9)figure Figure 1
Table 1(p. 10)table Table 1
Table 2(p. 11)table Table 2
Figure 2(p. 15)figure Figure 2
Figure 3(p. 16)figure Figure 3
Figure 4(p. 17)figure Figure 4
Figure 5(p. 18)figure Figure 5
Figure 6(p. 19)figure Figure 6
Figure 7(p. 21)figure Figure 7
Table 3(p. 22)table Table 3
Figure 8(p. 23)figure Figure 8
Figure 9(p. 24)figure Figure 9
Figure 10(p. 25)figure Figure 10
Figure 11(p. 26)figure Figure 11
Figure 12(p. 27)figure Figure 12

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