The Role of Negatively Charged Groups in Antimicrobial Cationic Peptide Mimics: Insights into Membrane Interactions.

In this study, we explore cationic amphiphilic methacrylate copolymers incorporating both positively charged AEMA and negatively charged PAMA functional groups, focusing on their interactions with bacterial membranes. Aggregation studies reveal that electrostatic interactions drive the formation of stable polymer aggregates, with block copolymers forming micelle-like structures and random copolymers exhibiting a more uniform distribution. These ternary polymers preferentially interact with deep lipid-packing defects in bacterial membranes, stabilizing and expanding these defects, while shallow defects remain largely unaffected due to the unfavorable interaction of anionic groups with lipid headgroups. The role of interfacial water is also critical, as hydration layers surrounding anionic groups shield them from electrostatic repulsion, enabling deeper penetration into the membrane. Comparative analyses highlight the advantages of anionic-containing polymers over previously studied polar-containing systems, which predominantly engage shallow defects and exhibit limited structural adaptability near membranes. These findings underscore the role of anionic residues in enabling adaptable AMP conformations, enhanced membrane engagement, and effective disruption mechanisms, providing valuable insights for the design of biomimetic antimicrobial polymers incorporating different functional groups.