title: Reorientation and dimerization of the membrane-bound antimicrobial peptide PGLa from microsecond all-atom MD simulations.
abstract: The membrane-active antimicrobial peptide PGLa from Xenopus laevis is known from solid-state (2)H-, (15)N-, and (19)F-NMR spectroscopy to occupy two distinct α-helical surface adsorbed states in membranes: a surface-bound S-state with a tilt angle of ~95° at low peptide/lipid molar ratio (P/L = 1:200), and an obliquely tilted T-state with a tilt angle of 127° at higher peptide concentration (P/L = 1:50). Using a rapid molecular-dynamics insertion protocol in combination with microsecond-scale simulation, we have characterized the structure of both states in detail. As expected, the amphiphilic peptide resides horizontally on the membrane surface in a monomeric form at a low P/L, whereas the T-state is seen in the simulations to be a symmetric antiparallel dimer, with close contacts between small glycine and alanine residues at the interface. The computed tilt angles and azimuthal rotations, as well as the quadrupolar splittings predicted from the simulations agree with the experimental NMR data. The simulations reveal many structural details previously inaccessible, such as the immersion depth of the peptide in the membrane and the packing of the dimerization interface. The study highlights the ability and limitations of current state-of-the-art multimicrosecond all-atom simulations of membrane-active peptides to complement experimental data from solid-state NMR.
authors.affiliation: Institute of Natural Sciences, Shanghai Jiao Tong University, Shanghai, China. Electronic address: jakob@ulmschneider.com.
authors.forename: Jakob P
authors.initials: JP
authors.lastname: Ulmschneider
authors.affiliation: Oak Ridge National Laboratory, Oak Ridge, Tennessee.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Smith
authors.affiliation: Department of Biophysics, University of London Birkbeck, London, United Kingdom.
authors.forename: Martin B
authors.initials: MB
authors.lastname: Ulmschneider
authors.affiliation: Institute of Biological Interfaces (IBG-2), Karlsruhe Institute of Technology, Karlsruhe, Germany; Institute of Organic Chemistry and CFN, Karlsruhe Institute of Technology, Karlsruhe, Germany.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Ulrich
authors.affiliation: Institute of Biological Interfaces (IBG-2), Karlsruhe Institute of Technology, Karlsruhe, Germany.
authors.forename: Erik
authors.initials: E
authors.lastname: Strandberg
mesh_terms: D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000378:metabolism*; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D013499:Surface Properties; D013997:Time Factors; D029867:Xenopus Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D023181:Antimicrobial Cationic Peptides; D008051:Lipid Bilayers; D029867:Xenopus Proteins