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Role of Peptide Associations in Enhancing the Antimicrobial Activity of Adepantins: Comparative Molecular Dynamics Simulations and Design Assessments

Overview
Journal Int J Mol Sci
Publisher MDPI
Date 2024 Nov 27
PMID 39596078
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Abstract

Adepantins are peptides designed to optimize antimicrobial biological activity through the choice of specific amino acid residues, resulting in helical and amphipathic structures. This paper focuses on revealing the atomistic details of the mechanism of action of Adepantins and aligning design concepts with peptide behavior through simulation results. Notably, Adepantin-1a exhibits a broad spectrum of activity against both Gram-positive and Gram-negative bacteria, while Adepantin-1 has a narrow spectrum of activity against Gram-negative bacteria. The simulation results showed that one of the main differences is the extent of aggregation. Both peptides exhibit a strong tendency to cluster due to the amphipathicity embedded during design process. However, the more potent Adepantin-1a forms smaller aggregates than Adepantin-1, confirming the idea that the optimal aggregations, not the strongest aggregations, favor activity. Additionally, we show that incorporation of the cell penetration region affects the mechanisms of action of Adepantin-1a and promotes stronger binding to anionic and neutral membranes.

References
1.
Walters R, Degrado W . Helix-packing motifs in membrane proteins. Proc Natl Acad Sci U S A. 2006; 103(37):13658-63. PMC: 1564267. DOI: 10.1073/pnas.0605878103. View

2.
Sarig H, Rotem S, Ziserman L, Danino D, Mor A . Impact of self-assembly properties on antibacterial activity of short acyl-lysine oligomers. Antimicrob Agents Chemother. 2008; 52(12):4308-14. PMC: 2592853. DOI: 10.1128/AAC.00656-08. View

3.
Jhong J, Yao L, Pang Y, Li Z, Chung C, Wang R . dbAMP 2.0: updated resource for antimicrobial peptides with an enhanced scanning method for genomic and proteomic data. Nucleic Acids Res. 2021; 50(D1):D460-D470. PMC: 8690246. DOI: 10.1093/nar/gkab1080. View

4.
Lee J, Patel D, Stahle J, Park S, Kern N, Kim S . CHARMM-GUI Membrane Builder for Complex Biological Membrane Simulations with Glycolipids and Lipoglycans. J Chem Theory Comput. 2018; 15(1):775-786. DOI: 10.1021/acs.jctc.8b01066. View

5.
Mor A, Hani K, Nicolas P . The vertebrate peptide antibiotics dermaseptins have overlapping structural features but target specific microorganisms. J Biol Chem. 1994; 269(50):31635-41. View