The octapeptins are
lipopeptide antibiotics that are structurally similar to
polymyxins yet retain activity against
polymyxin-resistant Gram-negative pathogens, suggesting they might be used to treat recalcitrant
infections. However, the basis of their unique activity is unclear because of the difficulty in generating high-resolution experimental data of the interaction of
antimicrobial peptides with
lipid membranes. To elucidate these structure-activity relationships, we employed all-atom molecular dynamics simulations with umbrella sampling to investigate the conformational and energetic landscape of octapeptins interacting with bacterial outer membrane (OM). Specifically, we examined the interaction of
octapeptin C4 and FADDI-115, lacking a single
hydroxyl group compared with
octapeptin C4, with the
lipid A-
phosphoethanolamine modified OM of Acinetobacter baumannii
Octapeptin C4 and FADDI-115 both penetrated into the OM hydrophobic center but experienced different conformational transitions from an unfolded to a folded state that was highly dependent on the structural flexibility of their respective N-terminal fatty acyl groups. The additional
hydroxyl group present in the fatty acyl group of
octapeptin C4 resulted in the molecule becoming trapped in a semifolded state, leading to a higher free energy barrier for OM penetration. The free energy barrier for the translocation through the OM hydrophobic layer was ∼72 kcal/mol for
octapeptin C4 and 62 kcal/mol for FADDI-115. Our results help to explain the lower antimicrobial activity previously observed for
octapeptin C4 compared with FADDI-115 and more broadly improve our understanding of the structure-function relationships of octapeptins. These findings may facilitate the discovery of next-generation octapeptins against
polymyxin-resistant Gram-negative 'superbugs.'