Amyloidogenic peptides associated with neurodegeneration often have functional roles including fighting microbial infections, indicating a link between the amyloidogenic (AMY) and antimicrobial properties of these peptides. Uperin 3.5 is one such antimicrobial peptide (AMP) that also self assembles to form amyloid. Depending on the absence and presence of membranes, cross-β and a-helical fibrils are formed, respectively. This indicates that the membrane environment plays an active role in dictating the fate of peptide aggregation. To obtain a holistic picture an in-depth study of peptide-membrane interactions is essential.
Previous research has focused on Uperin 3.5 peptide behavior in solution or in the presence of bacterial membrane-mimetic surfaces. Here, we report the effect of a zwitterionic environment on the self-assembly of the Uperin 3.5 wt. peptide and provide insight into the molecular basis of aggregation as well as the antimicrobial properties. The zwitterionic, DPC (dodecyl phosphocholine) micelle was used to mimic eukaryotic membranes.
Classical (CMD) and Accelerated Molecular Dynamics (AMD) simulations, were used to investigate three possible mechanistic pathways of peptide-micelle interactions; (i) nine random coils interacting with a single micelle, (ii) twelve random coils with an existing seed (nucleus) present as aggregates, near the micelle, (iii) soluble aggregates (partial helices + coils) interacting with the DPC micelle. In all three simulations, the random coils were adsorbed gradually onto the micelle surface, which converted to stable alpha-helices. This altered the charge-distribution in micelle local-environment causing a beta-sheet-rich-dimer (formed in solution) to stably adsorb on micelle surface. This behaved as a precursor for amyloid and acted as a seed for peptides to associate, enhancing further aggregation. Unlike the anionic (SDS micelle) bacterial mimetic environment,[1] where peptides insert into the hydrophobic- micelle-core, in the DPC environment, peptides were retained at the micelle surface and oligomerized into amyloid-like structures. This indicates that the subtle electrostatic attraction of the zwitterionic micelle causes the peptide-peptide interactions to ‘win’ over the ‘peptide-micelle’ interactions. This leads to clustering of the peptide that prevents membrane lysis, and instead triggers self-assembly and amyloid formation. This study also sheds light on the underlying molecular mechanisms as to how AMPs might prevent host-cell-cytotoxicity.