Effect of histidine on the antimicrobial peptide maculatin 1.1 solution-state NMR and molecular dynamics simulation structures at different protonation states

The role of histidine in a helical peptide with membrane activity was investigated by modifying the parent antimicrobial peptide, maculatin 1.1, into its M2 variant. The M2 sequence has two extra histidines, and some residues were displaced to devise a greater hydrophilic groove. The effect of pH on the secondary structure and interactions with dodecylphosphocholine (DPC) micelles was determined using circular dichroism, solution-state NMR spectroscopy and molecular dynamics (MD) simulations. M2 transitioned from a random coil in buffer to an expected helical conformation in DPC micelles at both neutral and acidic pH, with both structures displaying a continuous hydrophilic groove. However, the helix was slightly bent at pH 7, but with protonated histidines at pH 5, a straight helix was observed. MD simulations showed that M2 was deeper into the micelle core with uncharged histidines at pH 7 and more exposed to water at pH 5. Overall, the M2 peptide showed moderate pH-sensitive behaviour akin to observed known histidine-rich membrane-active peptides, and further investigation within more realistic membrane environments will be necessary to determine its potential for pH-mediated activity.