AlphaFold with conformational sampling reveals the structural landscape of homorepeats

IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
David Fernandez Bonet, Shahrayar Ranyai, Luay Aswad, David P. Lane, Marie Arsenian-Henriksson, Michael Landreh, Dilraj Lama
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引用次数: 0

Abstract

Homorepeats are motifs with reiterations of the same amino acid. They are prevalent in proteins associated with diverse physiological functions but also linked to several pathologies. Structural characterization of homorepeats has remained largely elusive, primarily because they generally occur in the disordered regions or proteins. Here, we address this subject by combining structures derived from machine learning with conformational sampling through physics-based simulations. We find that hydrophobic homorepeats have a tendency to fold into structured secondary conformations, while hydrophilic ones predominantly exist in unstructured states. Our data show that the flexibility rendered by disorder is a critical component besides the chemical feature that drives homorepeats composition toward hydrophilicity. The formation of regular secondary structures also influences their solubility, as pathologically relevant homorepeats display a direct correlation between repeat expansion, induction of helicity, and self-assembly. Our study provides critical insights into the conformational landscape of protein homorepeats and their structure-activity relationship.

Abstract Image

带有构象取样功能的 AlphaFold 揭示了同源重复序列的结构景观
同源重复是指相同氨基酸的重复。它们普遍存在于与多种生理功能相关的蛋白质中,但也与多种病症有关。同源重复序列的结构特征在很大程度上仍然难以确定,这主要是因为它们通常出现在蛋白质的无序区域。在这里,我们通过基于物理的模拟,将机器学习得出的结构与构象取样相结合,解决了这一问题。我们发现,疏水性同源蛋白倾向于折叠成结构化的次级构象,而亲水性同源蛋白则主要存在于非结构化状态。我们的数据表明,除了化学特征之外,无序所带来的灵活性也是促使同源中继物组成趋向亲水性的关键因素。规则二级结构的形成也会影响它们的溶解度,因为与病理相关的同源中继物在重复扩展、螺旋诱导和自组装之间显示出直接的相关性。我们的研究为了解蛋白质同源中继蛋白的构象格局及其结构-活性关系提供了重要见解。
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来源期刊
Structure
Structure 生物-生化与分子生物学
CiteScore
8.90
自引率
1.80%
发文量
155
审稿时长
3-8 weeks
期刊介绍: Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.
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