Role of Lipid Packing Defects in Determining Membrane Interactions of Antimicrobial Polymers.

Understanding the emergence and role of lipid packing defects in the detection and subsequent partitioning of antimicrobial agents into bacterial membranes is essential for gaining insights into general antimicrobial mechanisms. Herein, using methacrylate polymers as a model platform, we investigate the effects of inclusion of various functional groups in the biomimetic antimicrobial polymer design on the aspects of lipid packing defects in model bacterial membranes. Two antimicrobial polymers are considered: ternary polymers composed of cationic, hydrophobic, and polar moieties and binary polymers with only cationic and hydrophobic moieties. We find that differing modes of insertion of these two polymers lead to different packing defects in the bacterial membrane. While insertion of both binary and ternary polymers leads to an enhanced number of deep defects in the upper leaflet, shallow defects are moderately enhanced upon interaction with ternary polymers only. We provide conclusive evidence that insertion of antimicrobial polymers in bacterial membrane is preceded by sensing of interfacial lipid packing defects. Our simulation results show that the hydrophobic groups are inserted at a single colocalized deep defect site for both binary and ternary polymers. However, the presence of polar groups in the ternary polymers use the shallow defects close to the lipid-water interface, in addition, to insert into the membrane, which leads to a more folded conformation of the ternary polymer in the membrane environment, and hence a different membrane partitioning mechanism compared to the binary polymer, which acquires an amphiphilic conformation.