Metastable alpha-rich and beta-rich conformations of small Aβ42 peptide oligomers.

IF 2.8 4区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Proteins-Structure Function and Bioinformatics Pub Date : 2025-08-01 Epub Date: 2023-04-10 DOI:10.1002/prot.26495

Phuong H Nguyen, Fabio Sterpone, Philippe Derreumaux

引用次数: 0

Abstract

Probing the structures of amyloid-β (Aβ) peptides in the early steps of aggregation is extremely difficult experimentally and computationally. Yet, this knowledge is extremely important as small oligomers are the most toxic species. Experiments and simulations on Aβ42 monomer point to random coil conformations with either transient helical or β-strand content. Our current conformational description of small Aβ42 oligomers is funneled toward amorphous aggregates with some β-sheet content and rare high energy states with well-ordered assemblies of β-sheets. In this study, we emphasize another view based on metastable α-helix bundle oligomers spanning the C-terminal residues, which are predicted by the machine-learning AlphaFold2 method and supported indirectly by low-resolution experimental data on many amyloid polypeptides. This finding has consequences in developing novel chemical tools and to design potential therapies to reduce aggregation and toxicity.

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小α β42肽寡聚物的亚稳态富α和富β构象。

在聚集的早期阶段探测淀粉样蛋白-β (Aβ)肽的结构在实验和计算上是极其困难的。然而，这一知识是极其重要的，因为小的低聚物是最有毒的物种。a - β42单体的实验和模拟指向具有瞬时螺旋或β链含量的随机线圈构象。我们目前对小的Aβ42低聚物的构象描述是向具有一些β片含量的无定形聚集体和具有有序β片组装的罕见高能态倾斜的。在这项研究中，我们强调了基于跨越c端残基的亚稳态α-螺旋束低聚物的另一种观点，这是通过机器学习AlphaFold2方法预测的，并间接得到了许多淀粉样蛋白多肽的低分辨率实验数据的支持。这一发现对开发新的化学工具和设计潜在的治疗方法以减少聚集和毒性具有重要意义。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Proteins-Structure Function and Bioinformatics 生物-生化与分子生物学

CiteScore

5.90

自引率

3.40%

发文量

172

审稿时长

3 months

期刊介绍： PROTEINS : Structure, Function, and Bioinformatics publishes original reports of significant experimental and analytic research in all areas of protein research: structure, function, computation, genetics, and design. The journal encourages reports that present new experimental or computational approaches for interpreting and understanding data from biophysical chemistry, structural studies of proteins and macromolecular assemblies, alterations of protein structure and function engineered through techniques of molecular biology and genetics, functional analyses under physiologic conditions, as well as the interactions of proteins with receptors, nucleic acids, or other specific ligands or substrates. Research in protein and peptide biochemistry directed toward synthesizing or characterizing molecules that simulate aspects of the activity of proteins, or that act as inhibitors of protein function, is also within the scope of PROTEINS. In addition to full-length reports, short communications (usually not more than 4 printed pages) and prediction reports are welcome. Reviews are typically by invitation; authors are encouraged to submit proposed topics for consideration.