Synergistic Antimicrobial Mechanism of the Ultrashort Antimicrobial Peptide R3W4V with a Tadpole-like Conformation,Journal of Chemical Information and Modeling

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Synergistic Antimicrobial Mechanism of the Ultrashort Antimicrobial Peptide R3W4V with a Tadpole-like Conformation
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2024-08-26 , DOI: 10.1021/acs.jcim.4c01100
Zanxia Cao ₁ , Zhihong Shi ₁ , Mingqiong Tong ₂ , Dongying Yang ₂ , Lei Liu ₁

Affiliation

Antimicrobial peptides (AMPs) are promising candidates in combating multidrug-resistant microorganisms because of their unique mode of action. Among these peptides, ultrashort AMPs (USAMPs) possess sequences containing less than 10 amino acids and have some advantages over traditional AMPs. However, one of the main limitations of designing novel and highly active USAMPs is that their mechanism of action at the molecular level is not well-known. In this article, we report the antimicrobial mechanism of the USAMP verine (R₃W₄V) with high antibacterial activity against Escherichia coli. Here, by using well-tempered bias-exchange metadynamics simulations and long-time conventional molecular dynamics simulations, we evaluated whether verine exhibits the same antimicrobial mode of action as that of traditional AMPs. The single verine-membrane system exhibited a relatively flat surface with multiple shallow minima separated by very small energy barriers and adopted highly dynamic structural ensembles. Although the verine sequence is very short, it can still exist briefly in the center of the cell membrane in a transmembrane state. As the concentration of verine increased, the transmembrane conformation was relatively stabilized in the membrane center or proceeded toward the membrane bottom. The lipid bilayer membrane showed relatively large deformation, including the phospholipid head groups embedded inside the lipid hydrophobic center, accompanied by a flip-flop of some lipids. Simulation results indicated that verine has a specific mechanism of action different from that of traditional AMPs. Based on this antimicrobial mechanism of verine, we can design new high-potential USAMPs by enhancing the structural stability of the transmembrane state.

中文翻译：

蝌蚪构象超短抗菌肽R3W4V的协同抗菌机制

抗菌肽（AMP）因其独特的作用方式而成为对抗多重耐药微生物的有希望的候选者。其中，超短AMP（USAMP）具有少于10个氨基酸的序列，与传统AMP相比具有一些优势。然而，设计新型高活性 USAMP 的主要限制之一是它们在分子水平上的作用机制尚不清楚。在本文中，我们报道了对大肠杆菌具有高抗菌活性的 USAMP verine (R ₃ W ₄ V) 的抗菌机制。在这里，通过使用良好的偏差交换元动力学模拟和长期的传统分子动力学模拟，我们评估了 Verine 是否表现出与传统 AMP 相同的抗菌作用模式。单动物膜系统表现出相对平坦的表面，具有由非常小的能垒分隔的多个浅最小值，并采用高动态结构整体。虽然verine序列很短，但它仍然可以以跨膜状态短暂存在于细胞膜中央。随着维林浓度的增加，跨膜构象在膜中心相对稳定或向膜底部前进。脂质双层膜表现出较大的变形，包括嵌入脂质疏水中心内的磷脂头基，并伴有一些脂质的翻转。模拟结果表明，verine 具有不同于传统 AMP 的特定作用机制。基于维林的这种抗菌机制，我们可以通过增强跨膜状态的结构稳定性来设计新的高潜力USAMP。

更新日期：2024-08-29

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