Shandong Provincial Key Laboratory of Biophysics, Institute of Biophysics, Dezhou University, Dezhou 253023, China.
Langmuir. 2020 Dec 22;36(50):15331-15342. doi: 10.1021/acs.langmuir.0c02777. Epub 2020 Dec 9.
The ultrashort linear antimicrobial tetrapeptide BRBR-NH with an unnatural residue biphenylalanine (B) has potent and rapid antimethicillin-resistant (MRSA) activity but lacks hemolytic activity. The anti-MRSA activity of BRBR-NH is 8-fold more potent than that of WRWR-NH and 16-fold more potent than that of FRFR-NH. 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-NH, 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-NH, WRWR-NH, and FRFR-NH) 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-NH interacts weakly with the RBC membrane, while not all BRBR-NH can be adsorbed to the RBC membrane surface. The MD simulation results produced significant local membrane thinning of multiBRBR-NH 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-NH 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-NH aggregation surface result in a local disturbance of the membrane structure. It can be concluded that the high anti-MRSA activity of BRBR-NH is attributed to the aggregation of BRBR-NH on the membrane surface. On the other hand, WRWR-NH and FRFR-NH peptides tend to bind with the membrane surface in a monomeric form and cover the membrane surface in a carpet-like manner. Therefore, these results provide an advanced microscopic understanding of how hydrophobic interactions or hydrophobic residues affect the antimicrobial activity and mechanism of antimicrobial peptides (AMPs).
具有非天然残基联苯丙氨酸（B）的超短线性抗菌四肽 BRBR-NH 具有强大而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 的抗-MRSA 活性比 WRWR-NH 强 8 倍，比 FRFR-NH 强 16 倍。然而，通过取代不同的芳香族疏水性残基如何影响它们的抗菌活性和机制仍不清楚。在这项工作中，为了研究不同疏水性相互作用和膜选择性对 BRBR-NH 的影响，我们进行了多次长时间（1000ns）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（BRBR-NH、WRWR-NH 和 FRFR-NH）在不同肽脂比下的相互作用，还探索了膜和肽结构特征的变化。结合能结果表明，BRBR-NH 与 RBC 膜的相互作用较弱，并且并非所有 BRBR-NH 都能被吸附到 RBC 膜表面。MD 模拟结果表明，多 BRBR-NH 肽在革兰氏阳性细菌细胞膜中产生明显的局部膜变薄。对结构特征和肽-膜相互作用的深入分析表明，BRBR-NH 在膜表面的聚集在破坏细胞膜方面起着至关重要的作用。与观察到的局部膜变薄相结合，深入分析表明脂质双层与 BRBR-NH 聚集表面之间的相互作用导致膜结构的局部干扰。可以得出结论，BRBR-NH 的高抗-MRSA 活性归因于 BRBR-NH 在膜表面的聚集。另一方面，WRWR-NH 和 FRFR-NH 肽倾向于以单体形式与膜表面结合，并以地毯式方式覆盖膜表面。因此，这些结果提供了对疏水性相互作用或疏水性残基如何影响抗菌肽（AMP）的抗菌活性和机制的先进微观理解。
