Interactions of the designed antimicrobial peptide MB21 and truncated dermaseptin S3 with lipid bilayers: molecular-dynamics simulations

Abstract

Molecular-dynamics simulations covering 30 ns of both a natural and a synthetic antimicrobial peptide in the presence of a zwitterionic lipid bilayer were performed. In both simulations, copies of the peptides were placed in an alpha-helical conformation on either side of the bilayer about 10 A (1 A=0.1 nm) from the interface, with either the hydrophobic or the positively charged face of the helix directed toward the bilayer surface. The degree of peptide-lipid interaction was dependent on the starting configuration: surface binding and subsequent penetration of the bilayer was observed for the hydrophobically oriented peptides, while the charge-oriented peptides demonstrated at most partial surface binding. Aromatic residues near the N-termini of the peptides appear to play an important role in driving peptide-lipid interactions. A correlation between the extent of peptide-lipid interactions and helical stability was observed in the simulations. Insertion of the peptides into the bilayer caused a dramatic increase in the lateral area per lipid and decrease in the bilayer thickness, resulting in substantial disordering of the lipid chains. Results from the simulations are consistent with early stages of proposed mechanisms for the lytic activity of antimicrobial peptides. In addition to these 'free' simulations, 25 ns simulations were carried out with the peptides constrained at three different distances relative to the bilayer interface. The constraint forces are in agreement with the extent of peptide-bilayer insertion observed in the free simulations.

Molecular dynamics simulations of helical antimicrobial peptides in SDS micelles: What do point mutations achieve?

“…The restriction on the accessible time scales and the need for prior knowledge of binding conformations have hampered the predictive ability of these simulation efforts and this has attracted criticism that many such simulations are only of academic value. Simulations of absorption of helical peptides from the aqueous phase into the interface [9][10][11] have been partly successful in eliminating this shortcoming. Even in this simulation, the helical face on which the peptide binds depends on what part of the helix faces the interface in the starting simulation assembly.…”

“…Additionally, the area per lipid in model phospholipid bilayers relaxes on the order of tens of nanoseconds, and the response of the bilayers to peptide insertion is relatively sluggish. 10 Single simulations of peptides in bilayers consume immense computational resources, and this is why there are only scattered efforts of simulations of AMPs with lipid bilayers. In the current study, we have carried out long-time-scale molecular dynamics simulations of a helical AMP ovispirin-1 in a dodecylphosphocholine (DPC) micelle in an attempt to understand the molecular mechanism of action of the peptide and to develop a model that can alleviate some of the above shortcomings.…”

Effects of Acyl versus Aminoacyl Conjugation on the Properties of Antimicrobial Peptides

“…Various sequence modification methods attempted to modify natural peptides by deleting, adding, or replacing one or more residues or assemble chimeric peptides from segments of different natural peptides. They have been extensively applied to the study of cecropins, magainins, and melittins (39,43,47) and of dermaseptins (4,41,48). Finally, acylation of antimicrobial peptides proved to be a useful technique for improving antimicrobial characteristics (3,13,(32)(33)(34)55).…”

Insights into the membrane interaction mechanism and antibacterial properties of chensinin-1b

“…Trp residues have been widely reported to exhibit the unique property of being able to interact with the interfacial region of a membrane, facilitating anchoring of the peptide to the bilayer surface [21,22]. This special feature of Trp makes it a very interesting molecule for designing short chain antimicrobial peptides.…”