Reorientation and Dimerization of the Membrane-Bound Antimicrobial Peptide PGLa from Microsecond All-Atom MD Simulations

• Published in: Biophysical journal 2012-08, Vol.103 (3), p.472-482
• Main Authors: Ulmschneider, Jakob P., Smith, Jeremy C., Ulmschneider, Martin B., Ulrich, Anne S., Strandberg, Erik
• Format: Article
• Language: English
• Subjects: alanine; Amino Acid Sequence; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - metabolism; antimicrobial peptides; Cell Membrane - chemistry; Cell Membrane - metabolism; dimerization; Lipid Bilayers - chemistry; Lipid Bilayers - metabolism; Membrane; Membranes; molecular dynamics; Molecular Dynamics Simulation; Molecular Sequence Data; NMR; Nuclear magnetic resonance; nuclear magnetic resonance spectroscopy; Peptides; Protein Multimerization; Protein Structure, Secondary; Simulation; Surface Properties; Time Factors; Xenopus laevis; Xenopus Proteins - chemistry; Xenopus Proteins - metabolism
• ISSN: 0006-3495; 1542-0086
• DOI: 10.1016/j.bpj.2012.06.040

The membrane-active antimicrobial peptide PGLa from Xenopus laevis is known from solid-state 2H-, 15N-, and 19F-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.