title: Docking and molecular dynamics simulations of the ternary complex nisin2:lipid II.
abstract: Lanthionine antibiotics are an important class of naturally-occurring antimicrobial peptides. The best-known, nisin, is a commercial food preservative. However, structural and mechanistic details on nisin-lipid II membrane complexes are currently lacking. Recently, we have developed empirical force-field parameters to model lantibiotics. Docking and molecular dynamics (MD) simulations have been used to study the nisin2:lipid II complex in bacterial membranes, which has been put forward as the building block of nisin/lipid II binary membrane pores. An Ile1Trp mutation of the N-terminus of nisin has been modelled and docked onto lipid II models; the computed binding affinity increased compared to wild-type. Wild-type nisin was also docked onto three different lipid II structures and a stable 2:1 nisin:lipid II complex formed. This complex was inserted into a membrane. Six independent MD simulations revealed key interactions in the complex, specifically the N-terminal engagement of nisin with lipid II at the pyrophosphate and C-terminus of the pentapeptide chain. Nisin(2) inserts into the membrane and we propose this as the first step in pore formation, mediated by the nisin N-terminus-lipid II pentapeptide hydrogen bond. The lipid II undecaprenyl chain adopted different conformations in the presence of nisin, which may also have implications for pore formation.
authors.affiliation: School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
authors.forename: Sam
authors.initials: S
authors.lastname: Mulholland
authors.affiliation: School of Pharmacy, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2RD, UK.
authors.forename: Eleanor R
authors.initials: ER
authors.lastname: Turpin
authors.affiliation: School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: Boyan B
authors.initials: BB
authors.lastname: Bonev
authors.affiliation: School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Hirst
mesh_terms: D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009561:Nisin / Q000737:chemistry*; D014538:Uridine Diphosphate N-Acetylmuramic Acid / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D014538:Uridine Diphosphate N-Acetylmuramic Acid; C069249:muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol; D009561:Nisin