Interaction of the Antimicrobial Peptide Cyclo(RRWWRF) with Membranes by Molecular Dynamics Simulations

Abstract

Antimicrobial peptides have gained a lot of interest in recent years due to their potential use as a new generation of antibiotics. It is believed that this type of relatively short, amphipathic, cationic peptide targets the bacterial membrane, and destroys the chemical gradients over the membrane via formation of stable or transient pores. Here we use the NMR structure of cyclo(RRWWRF) in a series of molecular dynamics simulations in membranes at various peptide/lipid ratios. We observe that the NMR structure of the peptide is still stable after 100 ns simulation. At a peptide/lipid ratio of 2:128, the membrane is only a little affected compared to a pure dipalmitoylphosphatidylcholine lipid membrane, but at a ratio of 12:128, the water-lipid interface becomes more fuzzy, the water molecules can reach deeper into the hydrophobic core, and the water penetration free-energy barrier changes. Moreover, we observe that the area per lipid decreases and the deuterium order parameters increase in the presence of the peptide. We suggest that the changes in the hydrophobic core, together with the changes in the headgroups, result in an imbalance of the membrane and that it is thus not an efficient hydrophobic barrier in the presence of the peptides, independent of pore formation.

Structure of the Antimicrobial, Cationic Hexapeptide Cyclo(RRWWRF) and Its Analogues in Solution and Bound to Detergent Micelles

“…A more detailed description of a possible mode of action based on a molecular dynamics study of c-RW embedded in a lipid bilayer will be published. [25] In conclusion we have shown that c-RW undergoes a conformational change upon membrane binding. This results in an altered structure that is induced by the lipid environment, irrespective of the charge.…”

“…[27] However, backbone cyclization restricts the maximum possible length of peptide to about 25 , from the tip of the R2 side chain to that of the R5. If the hydrophobic core of the membrane were lined by the cluster of aromatic residues, which are only about 16 in length, this would result in a considerable hydrophobic mismatch with the membrane, which has a hydrophobic core of approximately 25-30 . Since such an arrangement would be highly unfavoura- ble, [25] it appears that this model cannot be used for the interpretation of the presented results; even though it seems to explain the effect of other helical peptides. Also, for other peptides that could potentially span the membrane in a barrel-stave-like fashion, cyclization makes membrane spanning unlikely without destroying their activity.…”

“…[24] We have investigated these interactions by molecular dynamics simulations as described in an accompanying paper. [25] For the analogues c-RY, c-KW and c-RNal peptides, the structures were determined in the DPC-micelle-bound form. Similar conformations of the backbone and the same orientation of the side chains with clustered aromatic residues gave rise to distinct amphipathic structures.…”

Interaction of W-Substituted Analogs of Cyclo-RRRWFW with Bacterial Lipopolysaccharides: the Role of the Aromatic Cluster in Antimicrobial Activity

“…The peptide backbone lies parallel to the lipid bilayer surface, the positively charged R residues interact with the phosphate groups of the lipids, and aromatic residues insert into the membrane (7). Lipid demixing and domain formation in 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)]-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine bilayers have been suggested as the basis for the selective antibacterial action of c-RW (8).…”

Structures of cyclic, antimicrobial peptides in a membrane‐mimicking environment define requirements for activity

“…We have recently determined the structure of the antimicrobial peptide cyclo-(Arg-Arg-Trp-Trp-ArgPhe) (c-RW) and several analogues using solution NMR spectroscopy and have described their potential interactions with a biological membrane using extensive molecular dynamic simulations [6,7]. The membranemimicking environment, in our case DPC micelles, leads to a change in the structure of the peptides as compared to their conformation in aqueous solution.…”