Document Type


Publication Date



In our ongoing quest to design effective antimicrobial peptides (AMPs), this study aimed to elucidate the mechanisms governing cyclic amphiphilic AMPs and their interactions with membranes. The objective was to discern the nature of these interactions and understand how peptide sequence and structure influence antimicrobial activity. We introduced modifications into the established cyclic AMP peptide, [W4R4], incorporating an extra aromatic hydrophobic residue (W), a positively charged residue (R), or the unique 2,5-diketopiperazine (DKP). This study systematically explored the structure–activity relationships (SARs) of a series of cyclic peptides derived from the [W4R4] scaffold, including the first synthesis and evaluation of [W4R4(DKP)]. Structural, dynamic, hydrophobic, and membrane-binding properties of four cyclic peptides ([W4R4], [W5R4], [W4R5], [W4R4(DKP)]) were explored using molecular dynamics simulations within a DOPC/DOPG lipid bilayer that mimics the bacterial membrane. The results revealed distinct SARs linking antimicrobial activity to parameters such as conformational plasticity, immersion depth in the bilayer, and population of the membrane binding mode. Notably, [W4R5] exhibited an optimal “activity/binding to the bacterial membrane” pattern. This multidisciplinary approach efficiently decoded finely regulated SAR profiles, laying a foundation for the rational design of novel antimicrobial peptides.


This article was originally published in Molecules, volume 28, in 2023. (1247 kB)
Supporting information: Table S1. Description of the obtained MD trajectories: number, length, starting structures, and the presence of functionally active membrane-bound states (apolar mode); Table S2. Structuring of the peptides in water and water–membrane environments as probed with MD simulations: occurrence (%MD) of β-turns; Figure S1. Distribution of hydrophobic/hydrophilic properties on the molecular surface of the peptides [W4R4], [W5R4], [W4R5], and [W4R4(DKP)]; Figure S2. µs-long MD simulations: different conformations of membrane-embedded states of the peptides [W4R4], [W5R4], [W4R5], and [W4R4(DKP)]; Figure S3. Two membrane binding modes (apolar and locked) of the peptide [W4R4(DKP)] are potentially important for its membrane activity.


The authors

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.



To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.