The dynamic action mechanism of small cationic antimicrobial peptides

Abstract

Antimicrobial peptides form part of the immune system as protection against the action of external pathogens. The differences that exist between mammalian and microbial cell membrane architectures are key aspects of the ability of these peptides to discriminate between pathogens and host cells. Given that the pathogen membrane is the non-specific target of these cationic peptides, different molecular mechanisms have been suggested to describe the rules that permit them to distinguish between pathogens and mammalian cells. In this context, and setting aside the old fashion idea that cationic peptides act through one mechanism alone, this work will provide insight into the molecular action mechanism of small antimicrobial peptides, based on molecular dynamics simulations of phospholipid bilayers that mimic different cell membrane architectures. After measuring different properties of these lipid bilayers, in the absence and presence of peptides, a four-step action mechanism was suggested on the basis of the formation of phospholipid rafts induced by the presence of these cationic peptides. Thus, this work shows how differences in the bending modulus (k(b)) of these lipid rafts and differences in the free energy profiles (ΔG(z)) associated with the insertion of these peptides into these lipid rafts are key aspects for explaining the action mechanism of these cationic peptides at the molecular level.

Small Peptides Derived from Penetratin as Antibacterial Agents

“…It is interesting to remark that these experimental results are in line with our model for the mechanisms of action of these compounds proposed on the basis of MD simulations and molecular modeling . On the other hand, our results also clearly show that antibacterial activity within the series is mainly dominated by amino acid residues composition.…”

“…Based on the results obtained from molecular dynamics simulations, we have recently proposed a four‐step molecular mechanism for these small cationic peptides acting as antibacterial agents . Such mechanism includes the following steps: Peptides folding and induction of the phospholipid segregation. Peptides protruding into domains with poor charged phospholipid content. Membrane collapse and pore formation. Peptides transposition and, then, the recovery of the bilayer structure. …”

“…Based on the results obtained from molecular dynamics simulations, we have recently proposed a four-step molecular mechanism for these small cationic peptides acting as antibacterial agents [28,29]. Such mechanism includes the following steps: Our simulations indicated that the existence of some patches in the membrane in which the insertion of peptides is more favorable than in others (from a thermodynamic point of view), together with the mechanical inhomogeneities associated with its lipid composition, seem to be a key factor in explaining the molecular activity of these small cationic peptides.…”

Accelerated molecular dynamics simulation analysis of MSI-594 in a lipid bilayer

“…It has been previously observed, both experimentally and theoretically, that the area per lipid is much lower for homogeneous lipid bilayer systems in the absence of any peptide. 42, 43 Experimental studies have suggested an average value of 63.6 Å for the area per lipid of POPC/POPG (7:3) bilayer. 44 Our control simulation in the absence of peptide also shows an average value of 62.74 ± 1.20 Å.…”

Effect of monoglycerides and fatty acids on a ceramide bilayer

“…The compressibility modulus of the gel phase ceramide 2 bilayer is reported to be relatively high, k A E 4000 dyne cm À1 , 11,37 which is practically an order of magnitude higher than for phospholipid bilayers in a liquid crystalline phase where k A values are found to be around 100-500 dyne cm À1 . 76,77 The k A values for mixed bilayers as a function of MG or FA concentration in the CER2 bilayer are presented in Fig. 7A and B, respectively.…”