The Mechanism of Antimicrobial Small-Cationic Peptides from Coarse-Grained Simulations

抗菌肽 分子动力学 化学 脂质双层 双层 生物物理学 氨基酸 阳离子聚合 小泡 磷脂酰甘油 肽序列 组合化学 生物化学 计算化学 生物 磷脂 有机化学 磷脂酰胆碱 基因
作者
Ezequiel N. Frigini,Rodolfo D. Porasso,Tamás Beke‐Somfai,J. J. López Cascales,Ricardo D. Enriz,Sergio Pantano
出处
期刊:Journal of Chemical Information and Modeling [American Chemical Society]
卷期号:63 (21): 6877-6889
标识
DOI:10.1021/acs.jcim.3c01348
摘要

Antimicrobial cationic peptides (AMPs) are excellent candidates for use as therapeutic antimicrobial agents. Among them, short peptides possessing sequences of 9-11 amino acids have some advantages over long-sequence peptides. However, one of the main limitations of short peptides is that their mechanism of action at the molecular level is not well-known. In this article, we report a model based on multiscale molecular dynamics simulations of short peptides interacting with vesicles containing palmitoyl-oleoyl-phosphatidylglycerol (POPG)/palmitoyl-oleoyl-phosphatidylethanolamine (POPE). Simulations using this approach have allowed us to understand the different behaviors of peptides with antimicrobial activity with respect to those that do not produce this effect. We found remarkable agreement with a series of experimental results directly supporting our model. Moreover, these results allow us to understand the mechanism of action at the molecular level of these short peptides. Our simulations suggest that mechanical inhomogeneities appear in the membrane, promoting membrane rupture when a threshold concentration of peptides adsorbed on the membrane is achieved. These results explain the high structural demand for these peptides to maintain a delicate balance between the affinity for the bilayer surface, a low peptide-peptide repulsion (in order to reach the threshold concentration), and an acceptable tendency to penetrate into the bilayer. This mechanism is different from those proposed for peptides with long amino acid sequences. Such information is very useful from the medicinal chemistry point of view for the design of new small antimicrobial peptides.
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