MOLECULAR DYNAMICS STUDY OF POLYBIA-MP1 ADSORPTION AND MEMBRANE PERTURBATION IN CANCER-MIMETIC BILAYERS

Antimicrobial peptides (AMPs) are short, predominantly cationic components of the immune system with broad-spectrum of activity. Their mechanism of action typically involves electrostatic and hydrophobic interactions with cell membranes, disrupting membrane integrity and potentially leading to lysis. Beyond their well-known antibiotic properties, AMPs have also shown promise in antiviral, antifungal, antiparasitic, and antitumor applications. Polybia-MP1 (MP1), extracted from the wasp Polybia-paulista, possesses a broad antimicrobial spectrum with low hemolytic and cytotoxic effects. Its selectivity for tumor cells is fundamentally attributed to the externalization of the phospholipids phosphatidylethanolamine (PE) and the anionic phosphatidylserine (PS) on the outer leaflet of these cells, in contrast to healthy cells where both lipids remain confined to the inner leaflet. This exposure facilitates electrostatic interactions that significantly enhance MP1's binding affinity, reportedly up to sevenfold for PS-containing membranes. Additionally, the exposure of PE increases membrane susceptibility to MP1-induced disruption by promoting the formation of larger transmembrane pores. PS and PE act synergistically: while PS optimizes initial binding, their combination amplifies membrane permeabilization and rupture. In this study, we employed molecular dynamics (MD) simulations to investigate the interaction and mechanism of action of MP1 on model membranes mimicking the composition of tumor cell membranes (PC:PS:PE 70:20:10). Initial simulations, with a single MP1 peptide positioned 10 Å from the membrane surface in a random coil conformation, revealed partial adsorption and minor disturbances in the bilayer, including local changes in thickness, curvature, and order parameter, suggesting initial permeability induction. Subsequently, starting from the partially adsorbed single-peptide system, a second MP1 peptide was introduced into the water phase. These simulations suggest potential cooperative effects between peptides and support the synergistic role of PS and PE in bilayer destabilization. This study provides molecular-level insights into how the selective interaction of Polybia-MP1 with PS and PE drives its lytic activity against cancer cell membranes.