摘要
细菌对抗生素的耐药性的发展已经导致人们关注抗菌肽 (AMPs)。AMP 的常见机制是破坏细菌膜的完整性。α-防御素人中性粒细胞肽-1 (HNP-1) 最容易获得的靶标之一是脂质 II。在本研究中，我们对人中性粒细胞防御素 1 进行了同源性建模和几何验证。然后，HNP-1 衍生肽 2Abz 14 S 29、2Abz 23 S 29的构象和理化性质和 HNP1ΔC18A，以及它们与脂质 II 的相互作用进行了计算研究。全蛋白预测模型的整体质量为 -5.14，其中超过 90% 的残基位于 Ramachandran 图中最受青睐和允许的区域。尽管 HNP-1 和 HNP1ΔC18A 被归类为不稳定肽，但基于不稳定指数值，2Abz 14 S 29和 2Abz 23 S 29是稳定的。分子对接显示肽和 HNP-1 与脂质 II 的相互作用模式相似。分子动力学模拟揭示了构象的整体稳定性，尽管修饰肽中氨基酸的波动相对高于 HNP-1。此外，HNP-1 和 2Abz 23的结合亲和力常数 (Kd)与脂质 II 复合的S 29比 2Abz 14 S 29和 HNP1ΔC18A 强 10 倍。总体而言，构象和相互作用模式的计算研究表明，与报告的实验研究中的 HNP-1 相比，衍生肽如何显示出相对相似的抗菌结果。与 HNP-1 相比，化学修饰不仅改善了衍生肽的物理化学性质，而且还保留了肽的相似模式和结合亲和力。
由 Ramaswamy H. Sarma 传达
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Computational evaluation of modified peptides from human neutrophil peptide 1 (HNP-1)
Abstract
The development of bacterial resistance toward antibiotics has been led to pay attention to the antimicrobial peptides (AMPs). The common mechanism of AMPs is disrupting the integrity of the bacterial membrane. One of the most accessible targets for α-defensins human neutrophil peptide-1 (HNP-1) is lipid II. In the present study, we performed homology modeling and geometrical validation of human neutrophil defensin 1. Then, the conformational and physicochemical properties of HNP-1 derived peptides 2Abz14S29, 2Abz23S29, and HNP1ΔC18A, as well as their interaction with lipid II were studied computationally. The overall quality of the predicted model of full protein was −5.14, where over 90% of residues were in the most favored and allowed regions in the Ramachandran plot. Although HNP-1 and HNP1ΔC18A were classified as unstable peptides, 2Abz14S29 and 2Abz23S29 were stable, based on the instability index values. Molecular docking showed similar interaction pattern of peptides and HNP-1 to lipid II. Molecular dynamic simulations revealed the overall stability of conformations, though the fluctuations of amino acids in the modified peptides were relatively higher than HNP-1. Further, the binding affinity constant (Kd) of HNP-1 and 2Abz23S29 in complex with lipid II was 10 times stronger than 2Abz14S29 and HNP1ΔC18A. Overall, computational studies of conformational and interaction patterns have signified how derived peptides could have displayed relatively similar antimicrobial results compared to HNP-1 in the reported experimental studies. Chemical modifications not only have improved the physicochemical properties of derived peptides compared to HNP-1, but also they have retained the similar pattern and binding affinity of peptides.
Communicated by Ramaswamy H. Sarma