BIOPHYM, Department of Macromolecular Physics, Instituto de Estructura de la Materia, IEM-CSIC, C/ Serrano 113 bis, Madrid 28006, Spain.
Department of Microbiology, University of Granada, C/ Fuentenueva s/n, Granada 18071, Spain.
J Chem Inf Model. 2021 Dec 27;61(12):6066-6078. doi: 10.1021/acs.jcim.1c00838. Epub 2021 Dec 7.
The AS-48 bacteriocin is a potent antimicrobial polypeptide with enhanced stability due to its circular sequence of peptidic bonds. The mechanism of biological action is still not well understood in spite of both the elucidation of the molecular structure some years ago and several experiments performed that yielded valuable information about the AS-48 bacterial membrane poration activity. In this work, we present a computational study at an atomistic scale to analyze the membrane disruption mechanism. The process is based on the two-stage model: (1) peptide binding to the bilayer surface and (2) membrane poration due to the surface tension exerted by the peptide. Indeed, the induced membrane tension mechanism is able to explain stable formation of pores leading to membrane disruption. The atomistic detail obtained from the simulations allows one to envisage the contribution of the different amino acids during the poration process. Clustering of cationic residues and hydrophobic interactions between peptide and lipids seem to be essential ingredients in the process. GLU amino acids have shown to enhance the membrane disrupting ability of the bacteriocin. TRP24-TRP24 interactions make also an important contribution in the initial stages of the poration mechanism. The detailed atomistic information obtained from the simulations can serve to better understand bacteriocin structural characteristics to design more potent antimicrobial therapies.
AS-48 细菌素是一种有效的抗菌多肽，由于其肽键的环状序列而具有增强的稳定性。尽管几年前已经阐明了分子结构，并进行了一些实验获得了有关 AS-48 细菌膜穿孔活性的有价值信息，但生物作用机制仍未得到很好的理解。在这项工作中，我们进行了一项原子尺度的计算研究来分析膜破坏机制。该过程基于两阶段模型：（1）肽与双层表面的结合，以及（2）由于肽施加的表面张力导致的膜穿孔。实际上，诱导的膜张力机制能够解释导致膜破坏的稳定孔的形成。从模拟中获得的原子细节允许人们设想在穿孔过程中不同氨基酸的贡献。阳离子残基的聚类和肽与脂质之间的疏水相互作用似乎是该过程的重要组成部分。GLU 氨基酸已被证明增强了细菌素的膜破坏能力。TRP24-TRP24 相互作用在穿孔机制的初始阶段也做出了重要贡献。从模拟中获得的详细原子信息可用于更好地了解细菌素的结构特征，以设计更有效的抗菌治疗方法。
