Membrane Translocation of Highly Charged Antimicrobial Peptides via Multi-Microsecond All-Atom Md Simulations

Abstract

We report the first computational description of the membrane translocation mechanism and pathway of two antimicrobial peptides, PGLa from X. laevis (charge +5), and maculatin from L. genimaculata (charge +2), via multi-microsecond MD simulations. At P/L=1:20-50, assembly of monomers into higher oligomeric aggregates, or the formation of pores, is not observed for either peptide. Instead, individual monomers are transported across the bilayer in a two-stage mechanism in which charged sidechains are separately translocated via assistance of other peptides. Transmembrane inserted water-free intermediate states are observed that are stable over many microseconds. Our proposed mechanism disagrees with earlier models of antimicrobial bilayer penetration, and suggests that translocation of highly charged peptides across a membrane is simpler than previously thought.View Large Image | View Hi-Res Image | Download PowerPoint Slide