Influence of Different Aromatic Hydrophobic Residues on the Antimicrobial Activity and Membrane Selectivity of BRBR-NH2 Tetrapeptide
Influence of Different Aromatic Hydrophobic Residues on the Antimicrobial Activity and Membrane Selectivity of BRBR-NH2 Tetrapeptide
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不同芳香族疏水残基对BRBR-NH(2)四肽抗菌活性和膜选择性的影响。
DOI：
10.1021/acs.langmuir.0c02777
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发表时间：
2020-12-22
期刊：
影响因子：
3.9
通讯作者：
Cao, Zanxia
中科院分区：
文献类型：
--
作者：
Liu, Lei;Zhao, Liling;Cao, Zanxia
具有非天然残基联苯丙氨酸（B）的超短线性抗微生物四肽BRBR-NH 2具有有效且快速的抗耐甲氧西林金黄色葡萄球菌（MRSA）活性，但缺乏溶血活性。BRBR-NH 2的抗MRSA活性是WRWR-NH 2的8倍，是FRFR-NH 2的16倍。然而，如何影响其抗菌活性和机制，通过不同的芳香族疏水残基的取代仍不清楚。在这项工作中，为了研究BRBR-NH 2的不同疏水相互作用和膜选择性的影响，我们进行了多个长时间（1000 ns）的分子动力学（MD）模拟，以研究红细胞（RBC）膜和革兰氏阳性细菌细胞膜与三种不同四肽的相互作用（BRBR-NH 2、WRWR-NH 2和FRFR-NH 2）在不同的肽和脂质比例下的变化，并探讨了肽的膜和结构特征的变化。结合能结果表明，BRBR-NH 2与红细胞膜的相互作用较弱，但并不是所有的BRBR-NH 2都能吸附在红细胞膜表面。MD模拟结果在革兰氏阳性细菌细胞膜中产生了multiBRBR-NH 2肽的显著局部膜变薄。对结构特征和肽-膜相互作用的深入分析表明，BRBR-NH 2在膜表面的聚集在细胞膜的破坏中起着至关重要的作用。结合观察到的局部膜变薄，深入分析表明，脂双层和BRBR-NH 2聚集表面之间的相互作用导致膜结构的局部扰动。结果表明，BRBR-NH 2的高抗MRSA活性是由于BRBR-NH 2在膜表面的聚集所致。另一方面，WRWR-NH 2和FRFR-NH 2肽倾向于以单体形式与膜表面结合，并以地毯状方式覆盖膜表面。为此;这些结果为疏水相互作用或疏水残基如何影响抗菌肽（AMP）的抗菌活性和机制提供了先进的微观理解。
The ultrashort linear antimicrobial tetrapeptide BRBR-NH2 with an unnatural residue biphenylalanine (B) has potent and rapid antimethicillin-resistant Staphylococcus aureus (MRSA) activity but lacks hemolytic activity. The anti-MRSA activity of BRBR-NH2 is 8-fold more potent than that of WRWR-NH2 and 16-fold more potent than that of FRFR-NH2. However, how to influence their antimicrobial activities and mechanisms through the substitution of different aromatic hydrophobic residues is still unclear. In this work, to study the effects of varying hydrophobic interactions and membrane selectivities of BRBR-NH2, we performed multiple long-time (1000 ns) molecular dynamics (MD) simulations to investigate the interactions of a red blood cell (RBC) membrane and a Gram-positive bacterial cell membrane with three different tetrapeptides (BRBR-NH2, WRWR-NH2, and FRFR-NH2) under different ratios of peptides and lipids and also explored the changes in the membrane and structural characteristics of peptides. The binding energy results show that BRBR-NH2 interacts weakly with the RBC membrane, while not all BRBR-NH2 can be adsorbed to the RBC membrane surface. The MD simulation results produced significant local membrane thinning of multiBRBR-NH2 peptides in the Gram-positive bacterial cell membrane. An in-depth analysis of structural features and peptide-membrane interactions suggests that the aggregation of BRBR-NH2 on the membrane surface plays a crucial role in the destruction of the cell membrane. Taken together with the observed local membrane thinning, the in-depth analysis demonstrated that the interactions between the lipid bilayer and the BRBR-NH2 aggregation surface result in a local disturbance of the membrane structure. It can be concluded that the high anti-MRSA activity of BRBR-NH2 is attributed to the aggregation of BRBR-NH2 on the membrane surface. On the other hand, WRWR-NH2 and FRFR-NH2 peptides tend to bind with the membrane surface in a monomeric form and cover the membrane surface in a carpet-like manner. Therefor; these results provide an advanced microscopic understanding of how hydrophobic interactions or hydrophobic residues affect the antimicrobial activity and mechanism of antimicrobial peptides (AMPs).