Molecular View of Biomimetic Peptide in Action with Membrane

Short-chain synthetically designed biomimetic peptides have recently emerged as the practical alternatives of naturally occurring antimicrobial peptides. A pertinent question in this regard is: how does the distinct molecular architecture of short synthetic peptides, compared to their relatively long and flexible natural antimicrobial counterpart, lead to potent membrane disruption ability ? Here, we address this question via computationally investigating the action of 10-residue-long {beta}-peptide, a low-molecular weight synthetically designed antimicrobial foldamer, with a bacterial membrane-mimicking phospholipid bilayer. The investigation demonstrates that, beyond a threshold peptide-concentration, this short biomimetic peptide undergoes spontaneous self-aggregation and membrane-adsorption and subsequently forms stable transmembrane pore inside the membrane via a cooperative fashion, leading to membrane-disruption via water-leakage. Interestingly, the pore-inducing ability is found to be elusive in a non-globally amphiphilic sequence isomer, displaying its strong sequence-selective action on membrane. The analysis reveals that, despite having a short helical frame-work, these synthetic peptides, once inside the membrane, are able to stretch themselves towards favourable potential contact with polar head groups and interfacial water layer, thereby facilitating membrane-spanning pore formation process. Taken together, this work brings out a distinct mechanism of membrane-activity of minimally designed synthetic biomimetic oligomers relative to the natural antimicrobial peptides.