Membrane Selectivity Mechanisms of the Antimicrobial Peptide Snakin-Z Against Prokaryotic and Eukaryotic Membrane Models.

Snakin-Z, a novel cationic antimicrobial peptide (AMP) derived from fruits, exhibits broad-spectrum antimicrobial activity against bacteria and fungi. Importantly, it displays minimal hemolytic activity toward human red blood cells (RBCs). Elucidating the molecular basis of membrane selectivity of Snakin-Z is essential for its development as a novel antimicrobial agent. In this study, all-atom molecular dynamics (MD) simulations were employed to provide detailed molecular insights into the interactions between Snakin-Z and bacterial, fungal, and RBC membrane models. The simulations revealed a helical-coil conformation for Snakin-Z, with its amphipathic structure, polarity, and residues such as Arg, Lys, Ser, and Tyr playing crucial roles in mediating selective interactions with the microbial membrane models. Specifically, Arg28, Lys29, and Arg3 were identified as playing a crucial role in mediating membrane binding and stability. Snakin-Z was observed to be deeply embedded in the and membrane models, followed by and RBC membrane models. A considerable thinning and strong disordering of , and membranes acyl chains were observed. The presence of cholesterol in the RBC membrane contributes to its resistance to Snakin-Z-mediated disruption. This study presents the first comprehensive investigation of the selective mechanism underlying the antimicrobial activity of Snakin-Z against bacterial membrane models. Our findings provide insights into the antimicrobial properties of Snakin-Z at the molecular level, highlighting its significant potential for use in the food and biotechnology industries as a promising alternative to conventional antibiotics and preservatives.