title: Structural dynamics of the cell wall precursor lipid II in the presence and absence of the lantibiotic nisin.
abstract: Representing a physiological "Achilles' heel", the cell wall precursor lipid II (LII) is a prime target for various classes of antibiotics. Over the years LII-binding agents have been recognized as promising candidates and templates in the search for new antibacterial compounds to complement or replace existing drugs. To elucidate the molecular structural basis underlying LII functional mechanism and to better understand if and how lantibiotic binding alters the molecular behavior of LII, we performed molecular dynamics (MD) simulations of phospholipid membrane-embedded LII in the absence and presence of the LII-binding lantibiotic nisin. In a series of 2×4 independent, unbiased 100ns MD simulations we sampled the conformational dynamics of nine LII as well as nine LII-nisin complexes embedded in an aqueous 150mM NaCl/POPC phospholipid membrane environment. We found that nisin binding to LII induces a reduction of LII mobility and flexibility, an outward shift of the LII pentapeptide, an inward movement of the LII disaccharide section, and an overall deeper insertion of the LII tail group into the membrane. The latter effect might indicate an initial step in adopting a stabilizing, scaffold-like structure in the process of nisin-induced membrane leakage. At the same time nisin conformation and LII interaction remain similar to the 1WCO LII-nisin NMR solution structure.
authors.affiliation: Computational Structural Biology, Department of Life Science Informatics B-IT, Life & Medical Sciences (LIMES) Institute, Rheinische Friedrich Wilhelms-University Bonn, Dahlmannstraße 2, 53113 Bonn, Germany.
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Koch
authors.affiliation: Computational Structural Biology, Department of Life Science Informatics B-IT, Life & Medical Sciences (LIMES) Institute, Rheinische Friedrich Wilhelms-University Bonn, Dahlmannstraße 2, 53113 Bonn, Germany.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Schmidt
authors.affiliation: Institute for Medical Microbiology, Immunology and Parasitology, Pharmaceutical Microbiology Unit, Meckenheimer Allee 168, Rheinische Friedrich-Wilhelms-University Bonn, 53115 Bonn, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Sahl
authors.affiliation: Biophysical Chemistry, Department of Physical and Theoretical Chemistry, Rheinische Friedrich Wilhelms-University Bonn, Wegelerstraße 12, 53115 Bonn, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kubitscheck
authors.affiliation: Computational Structural Biology, Department of Life Science Informatics B-IT, Life & Medical Sciences (LIMES) Institute, Rheinische Friedrich Wilhelms-University Bonn, Dahlmannstraße 2, 53113 Bonn, Germany. Electronic address: chkandt@mail.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Kandt
keywords: Antimicrobial peptides; Lipid II; Lipid membrane; Molecular dynamics simulation; Molecular modeling; Nisin