Molecular Dynamics Simulations of Indolicidin Association with Model Lipid Bilayers

Abstract

Identifying the mechanisms responsible for the interaction of peptides with cell membranes is critical to the design of new antimicrobial peptides and membrane transporters. We report here the results of a computational simulation of the interaction of the 13-residue peptide indolicidin with single-phase lipid bilayers of dioleoylphosphatidylcholine, distearoylphosphatidylcholine, dioleoylphosphatidylglycerol, and distearoylphosphatidylglycerol. Ensemble analysis of the membrane-bound peptide revealed that, in contrast to the extended, linear backbone structure reported for indolicidin in sodium dodecyl sulphate detergent micelles, the peptide adopts a boat-shaped conformation in both phosphatidylglycerol and phosphatidylcholine lipid bilayers, similar to that reported for dodecylphosphocholine micelles. In agreement with fluorescence and NMR experiments, simulations confirmed that the peptide localizes in the membrane interface, with the distance between phosphate headgroups of each leaflet being reduced in the presence of indolicidin. These data, along with a concomitant decrease in lipid order parameters for the upper-tail region, suggest that indolicidin binding results in membrane thinning, consistent with recent in situ atomic force microscopy studies.

Coupling Molecular Dynamics Simulations with Experiments for the Rational Design of Indolicidin-Analogous Antimicrobial Peptides

“…[41][42][43][44] Moreover, this process has been observed through atomic force microscopy/confocal microscopy studies of IL binding 29 and is supported by previous MD simulations. 30 Our long-timescale MD simulations, with a total simulation time of up to 4 μs, revealed extensive degrees of local membrane thinning that were distinct processes for the two types of lipid bilayers at different stages of their interactions with IL. Extensive membrane thinning occurred for the mixed POPG/POPC lipid bilayer upon the adsorption of IL, whereas it occurred for the pure-POPC lipid bilayer upon IL insertion.…”

“…These results, which can be understood partially in terms of the stronger electrostatic attraction between the anionic head groups of the mixed POPG/POPC lipid bilayer and IL, are consistent with previous MD simulations. 30 …”

“…28 Recently, Shaw et al reported their observations of membrane thinning, due to interdigitation of the inner and outer leaflet of the membrane, upon interaction with IL; 29 they also observed this behavior in molecular dynamics (MD) simulations. 30 Other MD simulations have been performed to study how the side chains interactions of IL influence its structure near the membrane. 31 Although several mechanisms of action of IL have been proposed, the true mechanism remains unclear.…”

Recent Solid-State NMR Studies of Membrane-Bound Peptides and Proteins

“…MD simulation studies were performed to investigate whether the dynamic structures of various antimicrobial, antibacterial, and antibiotic peptides in membrane lipid-bilayer systems agree with those determined in solidstate NMR studies [55,[244][245][246][247][248][249][250]. MD simulation has been used to investigate the orientation of membrane-bound antimicrobial peptides (MB21 [244], indolicidin [245], BLT2 [246], CM15 [247], piscidin-1 [248], δ-lysin [249]), an antibacterial peptide (bovine LFampin [55]), neuropeptides (neuropeptides B and W [250]), human immunodeficiency virus fusion peptides (T-1249 [251], FP-16 and -23 [252], and VP1 [253]), and transmembrane peptides (gramicidin A [254], M2 [255], carnobacteriocin B2 [256], TM2 [257], human islet amyloid polypeptide [258], human serum paraoxonase 1 [259], and gaduscidin-1 and -2 [260]) in zwitterionic or anionic membrane lipid bilayers.…”

“…MD simulation has been used to investigate the orientation of membrane-bound antimicrobial peptides (MB21 [244], indolicidin [245], BLT2 [246], CM15 [247], piscidin-1 [248], δ-lysin [249]), an antibacterial peptide (bovine LFampin [55]), neuropeptides (neuropeptides B and W [250]), human immunodeficiency virus fusion peptides (T-1249 [251], FP-16 and -23 [252], and VP1 [253]), and transmembrane peptides (gramicidin A [254], M2 [255], carnobacteriocin B2 [256], TM2 [257], human islet amyloid polypeptide [258], human serum paraoxonase 1 [259], and gaduscidin-1 and -2 [260]) in zwitterionic or anionic membrane lipid bilayers. The membrane-bound peptides were inserted into the membrane perpendicular to the membrane surface, with the C-or N-terminus toward the inside of the membrane.…”