[论文解读] Physicochemical Features and Peculiarities of Interaction of Antimicrobial Peptides with the Membrane

Malak Pirtskhalava, Boris Vishnepolsky+1 more|arXiv (Cornell University)|May 8, 2020

Antimicrobial Peptides and Activities参考文献 150被引用 5

一句话总结

本综述综合了调控抗菌肽（AMP）与微生物膜相互作用的物理化学原理，强调疏水性、两亲性和残基分布是决定其作用机制与效力的关键因素。文章主张通过物理化学编码AMP序列，以实现对新型肽类抗生素的精确、计算模拟分类与从头设计，从而降低耐药性风险。

ABSTRACT

Antimicrobial peptides (AMPs) are anti-infectives that have potential as a novel and untapped class of biotherapeutics. Modes of action of antimicrobial peptides imply interaction with cell envelope. Comprehensive understanding of peculiarities of interactions of antimicrobial peptides with cell envelope is necessary to perform the task-oriented design of new biotherapeutics, against which for microbes it is hard to work out resistance. In order to enable a de novo design with low costs and in high throughput, in silico predictive models have to be required. To develop the performant predictive model, comprehensive knowledge on mechanisms of action of AMPs has to be possessed. The last knowledge will allow us to encode amino acid sequences expressively and to get success to the choosing of the accurate classifier of AMPs. A shared protective layer of microbial cells is inner, plasmatic membrane. The interaction of AMP with a biological membrane (native and/or artificial) is the most comprehensively studied. We provide a review of mechanisms and results of interaction of AMP with the cell membrane, relying on the survey of physicochemical, aggregative and structural features of AMPs. Potency and mechanism of action of AMP have presented in the terms of amino acid compositions and distributions of the polar and apolar residues along the chain, that is in such physicochemical features of peptides as the hydrophobicity, hydrophilicity, and amphiphilicity. Many different approaches were used to classify AMPs. The survey of the knowledge on sequences, structures, and modes of actions of AMP, allows concluding that, only the physicochemical features of AMPs give the capability to perform the unambiguous classification. Comprehensive knowledge of physicochemical features of AMP is necessary to develop task-oriented methods of design of peptide-based antibiotics de novo.

研究动机与目标

• 系统整理调控抗菌肽（AMP）与生物膜相互作用的物理化学特性。
• 识别基于序列的物理化学描述符（如疏水性、亲水性和两亲性），以预测AMP的活性与作用机制。
• 建立基于物理化学编码的计算模拟分类基础，以支持从头药物设计。
• 通过面向任务、机制驱动的肽设计，降低微生物进化出耐药性的潜力。
• 提供一个全面的框架，通过物理化学建模将AMP序列特征转化为功能结果。

提出的方法

• 系统回顾AMP-膜相互作用的实验与计算研究。
• 分析AMP序列中极性与非极性残基的组成与分布。
• 评估物理化学参数：疏水性、亲水性和两亲性作为预测特征。
• 整合结构、聚集性和物理化学数据，识别AMP功能的一致性模式。
• 利用基于序列的物理化学编码，支持机器学习分类器的开发以实现AMP预测。
• 比较多种AMP分类方法，基于物理化学特征识别最可靠、无歧义的方法。

实验结果

研究问题

• RQ1 哪些抗菌肽的物理化学特性与膜破坏活性关联最强？
• RQ2 疏水性与亲水性残基的空间分布如何影响AMP的作用机制？
• RQ3 仅依靠物理化学描述符能否实现对不同家族与作用模式AMP的无歧义分类？
• RQ4 物理化学编码在支持高通量、计算模拟的新型AMP设计方面能发挥多大作用？
• RQ5 膜特异性物理化学相互作用在决定AMP效力与选择性方面起什么作用？

主要发现

• 疏水性、亲水性和两亲性是预测AMP活性与机制最具预测力的物理化学特征。
• 肽链上极性与非极性残基的分布是膜相互作用与孔道形成的关键决定因素。
• 仅依靠物理化学特征即可提供稳健且无歧义的AMP分类基础，优于基于序列或仅基于结构的方法。
• 全面掌握这些特征可支持开发用于从头AMP设计的预测性计算模型。
• 膜作用机制的最佳理解应基于物理化学原理，而非仅依赖序列同源性。
• 将物理化学描述符整合到分类系统中，可支持低耐药潜力抗生素的理性设计。