Exploring the Insertion Mechanism of SVS-1 β-Hairpin Peptide into an Anionic Lipid Bilayer

Abstract

Antimicrobial peptides (AMPs) are ubiquitous in many biological systems and act as host defenses against microbial pathogens. Existing theories on how AMPs insert and cause pore formation still lack mechanistic detail. In this study, we investigate the insertion mechanism of SVS-1 (KVKVKVKVDPPTKVKVKVK), an anti-cancer beta-hairpin peptide, into an anionic lipid bilayer using atomistic molecular dynamics (MD) simulations.There is an energy barrier needed to overcome the strong electrostatic interactions of positive peptide sidechains and negatively charged lipid head groups. By comparing the folding of SVS-1 in charged and uncharged lipid bilayers, we found that folding occurs at different rates and lead to different secondary structures. The introduction of one valine sidechain site into the bilayer promotes folding at the surface. We see correct folding and misfolding in the forms of a beta bulge and partial α-helical formation in our simulations. We infer these single molecule structures as intermediates and suggest a cooperative peptide effect will induce correct folding and insertion. Further insight gained from our studies can potentially aid in design of novel AMPs as therapeutic or cancer targets and classify the mechanisms of insertion and membrane disruption.