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 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.affiliation: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark , Odense, Denmark.|School of Chemistry, University of Southampton , Highfield, Southampton SO17 1BJ, U.K.
authors.forename: Sarah
authors.initials: S
authors.lastname: Witzke
authors.affiliation: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark , Odense, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Petersen
authors.affiliation: Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory , 7000 East Avenue, Livermore, California 94550, United States.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Carpenter
authors.affiliation: School of Chemistry, University of Southampton , Highfield, Southampton SO17 1BJ, U.K.
authors.forename: Syma
authors.initials: S
authors.lastname: Khalid
mesh_terms: D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D013203:Staphylococcal Infections / Q000378:metabolism* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D014538:Uridine Diphosphate N-Acetylmuramic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
chemical_list: D010455:Peptides; D014538:Uridine Diphosphate N-Acetylmuramic Acid; C069249:muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol; C504857:plectasin