Understanding Antimicrobial\nPeptide Synergy: Differential\nBinding Interactions and Their Impact on Membrane Integrity

Research on antimicrobial peptides (AMPs) has been conducted\nas\na solution to overcome antibiotic resistance. In particular, the synergistic\neffect that appears when two or more AMPs are used in combination\nhas been observed. To find an effective synergistic combination, it\nis necessary to understand the underlying mechanism. However, a consistent\nexplanation for this phenomenon has not yet been provided due to limitations\nin experimentally determining or predicting the structure of the heteroaggregates\nformed by the interactions between different AMPs and the interaction\nof the aggregate surface with the lipid membrane surface. In this\nstudy, we conducted molecular dynamics simulations for two heterogeneous\naggregates of melittin–indolicidin and pexiganan–indolicidin\nto observe their structures in the solution phase and their interactions\nwith the lipid membrane. We aimed to determine how the surfaces of\nthese aggregates interact with the lipid membrane. Due to the different\namino acid residue sequence characteristics of melittin and pexiganan,\nwe found that when the two AMPs bind to indolicidin, they form aggregates\nwith completely different structural characteristics. Accordingly,\nthe sequence characteristics of pexiganan, which exhibits a relatively\nunstable structure compared to melittin in aqueous solution or on\nlipid membranes, allow for a more stable interaction with the lipid\nmembrane when forming aggregates with indolicidin, effectively inhibiting\nthe integrity of the lipid membranes. We also found that the amino\nacid residues forming the surface of the AMP aggregate show differential\nbinding strengths to different lipid species forming the lipid membrane,\nthereby disrupting the membrane in a way that weakens its integrity.\nThrough this, we provided insight into the basic principle of how\nthe synergistic effect of AMPs occurs.