PGLa and Magainin 2 Can Porate Membranes via Transient Hourglass-Shaped Toroidal Pores

Antimicrobial resistance has emerged as a significant global public health concern, necessitating prompt and comprehensive attention. In response to this pressing challenge, antimicrobial peptides (AMPs), which are innate immune system components naturally synthesized by diverse organisms, hold potential as alternative therapeutic agents. However, a primary obstacle resides in the absence of effective experimental methodologies capable of investigating transient behaviors of membrane active peptides at the atomic scale. In this study, we have employed all-atom molecular dynamics (MD) simulations to elucidate the mechanisms underlying the behavior of two magainin peptides and their equimolar mixture, namely PGLa and magainin 2 (Mag2). Despite extensive investigation spanning decades, the fundamental mechanisms governing these peptides are still not fully understood. Our findings demonstrate that simulation time scales over 10 μs can capture the formation of pores within bacterial model membrane mimics and obtain comprehensive insights into the spontaneous self-assembly of magainin peptides. An hourglass pore model is proposed to explain their transient membrane perforation, where peptides self-assemble to support the pore structure from both membrane leaflets as double stacks. Atomistic MD simulations provide an unprecedented direct view on selective transmembrane binding, pore formation, pore fluctuation and ultimately pore closure. These insights offer a new promising path for the development of peptide-based therapeutics tailored to combat bacterial infections.