Structure-activity relationship of peptide conjugates derived from BP100 and insights into their interactions with lipid membranes by NMR and MD simulations.

Antimicrobial and plant defence elicitor peptides have received attention on last decades as novel tools to combat bacterial plant diseases. We previously reported a library of peptide conjugates resulting from the combination of an antimicrobial peptide (, , or ) and a plant defence elicitor sequence (, , or ). From this library, we selected a set of 14 peptide conjugates including both highly and poorly active sequences and we performed a structure-activity relationship study by NMR and MD simulations. Analysis of their structure by NMR in 30% TFE-d and in zwitterionic DPC-d and anionic SDS-d micelles showed that the presence of an α-helix fragment together with a flexible random coil can be related to a high antibacterial activity and a low hemolysis. In contrast, the sequences with a rigid α-helix structure were low active and highly hemolytic. PRE-NMR experiments in presence of MnCl and 16-DSA revealed that the highly active peptides and interacted stronger with DPC-d micelles than the low active peptide . In the two former sequences this interaction took place through the α-helix region. From GaMD simulations of conducted in membranes composed of anionic DPPG lipids, after its electrostatic interaction, the peptide flipped and the hydrophobic residues were faced to the membrane triggering its insertion and also causing membrane thinning. Thus, the flexibility and moderate cationicity of seem to be crucial for its biological activity. These findings can help to establish the guidelines for future rational design of derivatives.