Faculty of Maritime Studies, University of Split, 21000 Split, Croatia.
Department of Physics, Faculty of Science, University of Split, 21000 Split, Croatia.
Int J Mol Sci. 2024 Nov 8;25(22):12009. doi: 10.3390/ijms252212009.
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.
阿德潘汀是通过选择特定氨基酸残基来优化抗菌生物活性的肽，从而形成螺旋和两亲性结构。本文重点揭示阿德潘汀作用机制的原子细节，并通过模拟结果将设计理念与肽行为进行对齐。值得注意的是，阿德潘汀-1a 对革兰氏阳性和革兰氏阴性菌均表现出广谱的活性，而阿德潘汀-1 对革兰氏阴性菌的活性谱较窄。模拟结果表明，主要区别之一在于聚集的程度。由于在设计过程中嵌入了两亲性，两种肽都表现出强烈的聚集倾向。然而，更有效的阿德潘汀-1a 形成的聚集体比阿德潘汀-1 小，这证实了这样一种观点，即最佳聚集，而不是最强的聚集，有利于活性。此外，我们还表明，细胞穿透区域的掺入会影响阿德潘汀-1a 的作用机制，并促进与阴离子和中性膜更强的结合。
