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

Biochemistry. 2016 Jun 14;55(23):3303-14. doi: 10.1021/acs.biochem.5b01315. Epub 2016 May 27.

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 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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Binding Sites
  • Cell Membrane / metabolism*
  • Models, Molecular
  • Molecular Dynamics Simulation*
  • Peptides / chemistry
  • Peptides / metabolism*
  • Protein Conformation
  • Staphylococcal Infections / metabolism*
  • Staphylococcal Infections / microbiology
  • Staphylococcus aureus / drug effects
  • Staphylococcus aureus / growth & development
  • Staphylococcus aureus / metabolism*
  • Uridine Diphosphate N-Acetylmuramic Acid / analogs & derivatives*
  • Uridine Diphosphate N-Acetylmuramic Acid / chemistry
  • Uridine Diphosphate N-Acetylmuramic Acid / metabolism

Substances

  • Peptides
  • Uridine Diphosphate N-Acetylmuramic Acid
  • muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol
  • plectasin