Modulation of free energy landscapes as a strategy for the design of antimicrobial peptides.
Modulation of free energy landscapes as a strategy for the design of antimicrobial peptides.
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DOI：
10.1007/s10867-022-09605-z
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发表时间：
2022-06
影响因子：
1.8
通讯作者：
Steinbach, Peter J.
中科院分区：
文献类型：
--
作者：
Hassan, Sergio A.;Steinbach, Peter J.
关键词：
抗菌肽的计算机设计是开发抗耐药菌新药的一个很有前途的研究领域。AMP天然存在于从细菌到人类的许多生物体中，这是一种经过时间考验的机制，使它们成为有吸引力的有效抗生素。根据环境，AMP可以表现出α-螺旋或β-折叠构象，两者的混合，或缺乏二级结构;它们可以是线性或环状的。预测它们的结构是具有挑战性的，但对于合理设计至关重要。有前途的AMP引线可以使用基本上两种方法开发：确定肽在水和膜环境中行为的物理化学机制的传统建模和基于知识的，例如，机器学习（ML）技术，利用不断增长的AMP数据库。在这里，我们探讨了两个最近ML设计的AMP的构象景观，表征这些景观对介质条件的依赖性，并确定介导蛋白质-膜结合的肽和膜景观的特征。对于这两种肽，我们观察到更大的构象多样性，在水性溶剂中比在极性较低的溶剂，和一个肽被认为是改变其构象更显着比其他溶剂的变化。我们的研究结果支持这样的观点，即响应于环境变化的结构重排是线性肽破坏膜结构的机制的核心。我们预计，通过ML的AMP的设计将受益于肽构象亚态的掺入，如这里用分子模拟定量的。在线版本包含补充材料，可通过10.1007/s10867-022-09605-z获得。
Computational design of antimicrobial peptides (AMPs) is a promising area of research for developing novel agents against drug-resistant bacteria. AMPs are present naturally in many organisms, from bacteria to humans, a time-tested mechanism that makes them attractive as effective antibiotics. Depending on the environment, AMPs can exhibit α-helical or β-sheet conformations, a mix of both, or lack secondary structure; they can be linear or cyclic. Prediction of their structures is challenging but critical for rational design. Promising AMP leads can be developed using essentially two approaches: traditional modeling of the physicochemical mechanisms that determine peptide behavior in aqueous and membrane environments and knowledge-based, e.g., machine learning (ML) techniques, that exploit ever-growing AMP databases. Here, we explore the conformational landscapes of two recently ML-designed AMPs, characterize the dependence of these landscapes on the medium conditions, and identify features in peptide and membrane landscapes that mediate protein-membrane association. For both peptides, we observe greater conformational diversity in an aqueous solvent than in a less polar solvent, and one peptide is seen to alter its conformation more dramatically than the other upon the change of solvent. Our results support the view that structural rearrangement in response to environmental changes is central to the mechanism of membrane-structure disruption by linear peptides. We expect that the design of AMPs by ML will benefit from the incorporation of peptide conformational substates as quantified here with molecular simulations. The online version contains supplementary material available at 10.1007/s10867-022-09605-z.
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影响因子：
3
作者：
Cardone, Antonio;Bornstein, Aaron;Pant, Harish C.;Brady, Mary;Sriram, Ram;Hassan, Sergio A.
通讯作者：
Hassan, Sergio A.
影响因子：
56.9
作者：
FRAUENFELDER, H;SLIGAR, SG;WOLYNES, PG
通讯作者：
WOLYNES, PG
影响因子：
3.3
作者：
Hassan, SA;Guarnieri, F;Mehler, EL
通讯作者：
Mehler, EL
DOI：
10.1073/pnas.82.15.5000
发表时间：
1985-01-01
影响因子：
11.1
作者：
ANSARI, A;BERENDZEN, J;YOUNG, RD
通讯作者：
YOUNG, RD
影响因子：
4.4
作者：
Hassan, Sergio A.
通讯作者：
Hassan, Sergio A.