Binding, Folding, and Insertion of a β-Hairpin Peptide at a Lipid Bilayer Surface: Molecular Dynamics Simulations

Abstract

Antimicrobial peptides (AMPs) are common in many biological systems and act as host defenses against microbial pathogens. Existing theories on how AMPs permeabilize lipid membranes still lack mechanistic detail. In this study, we used atomistic molecular dynamics (MD) simulations to investigate the interactions of SVS-1 (KVKVKVKVPDPLTKVKVKVK), an anti-cancer β-hairpin peptide, with a fully hydrated neutral POPC bilayer and a mixture of 1:1 anionic POPC/POPG bilayer. In agreement with experiment, peptides in simulation bind more strongly to anionic bilayers than to neutral bilayers. Unfolded peptides at the anionic surface were observed to undergo several folding and mis-folding pathways. Folded peptides at the surface did not spontaneously insert their hydrophobic faces into the bilayer on the 1 µs timescale, but kept their Lys-rich face downward toward the lipid head groups. Upon the application of sufficient surface tension, the peptides were observed to “flip and dip” into the bilayer within ∼100 ns. Pre-folded SVS-1 peptides were observed to insert in neutral membranes with ample surface tension, but remained at the surface or in solution if unfolded. We associate this insertion phenomenon to increased hydrophobic exposure of lipid tails due to tension. Our simulations suggest electrostatics interactions and hydrophobic exposure are key factors in witnessing an insertion event. The apparent absence of a pathway for a single peptide to produce a defect or pore in the bilayer suggests that the mechanism involves cooperative action of multiple peptides.