Kinetics of seeded protein aggregation: Theory and application.

IF 3.1 2区 化学 Q3 CHEMISTRY, PHYSICAL
Alexander J Dear, Georg Meisl, Jing Hu, Tuomas P J Knowles, Sara Linse
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引用次数: 0

Abstract

"Seeding" is the addition of preformed fibrils to a solution of monomeric protein to accelerate its aggregation into new fibrils. It is a versatile and widely used tool for scientists studying protein aggregation kinetics, as it enables the isolation and separate study of discrete reaction steps contributing to protein aggregation, specifically elongation and secondary nucleation. However, the seeding levels required to achieve dominating effects on each of these steps separately have been established largely by trial-and-error due in part to the lack of availability of integrated rate laws valid for moderate to high seeding levels and generally applicable to all common underlying reaction mechanisms. Here, we improve on a recently developed mathematical method based on Lie symmetries for solving differential equations and with it derive such an integrated rate law. We subsequently develop simple expressions for the amounts of seed required to isolate each step. We rationalize the empirical observation that fibril seeds must often be broken up into small pieces to successfully isolate elongation. We also derive expressions for average fibril lengths at different times in the aggregation reaction and explore different methods to break up fibrils. This paper will provide an invaluable reference for future experimental and theoretical studies in which seeding techniques are employed and should enable more sophisticated analyses than have been performed to date.

种子蛋白聚集动力学:理论与应用。
“播种”是将预先形成的原纤维添加到单体蛋白溶液中,以加速其聚集成新的原纤维。它是研究蛋白质聚集动力学的科学家广泛使用的通用工具,因为它可以分离和单独研究有助于蛋白质聚集的离散反应步骤,特别是延伸和二次成核。然而,在这些步骤中分别实现主导效应所需的播种水平主要是通过试错建立的,部分原因是缺乏适用于中高播种水平并普遍适用于所有常见潜在反应机制的综合速率规律。在这里,我们改进了最近发展的一种基于李对称的数学方法来求解微分方程,并利用它推导出这样一个积分速率定律。我们随后开发了分离每一步所需种子量的简单表达式。我们合理化的经验观察,原纤维种子必须经常被打破成小块,以成功地分离伸长。我们还推导了聚集反应中不同时间纤维平均长度的表达式,并探索了不同的分解纤维的方法。这篇论文将为未来的实验和理论研究提供宝贵的参考,在这些研究中,播种技术将被采用,并将使比迄今为止所进行的更复杂的分析成为可能。
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
Journal of Chemical Physics
Journal of Chemical Physics 物理-物理:原子、分子和化学物理
CiteScore
7.40
自引率
15.90%
发文量
1615
审稿时长
2 months
期刊介绍: The Journal of Chemical Physics publishes quantitative and rigorous science of long-lasting value in methods and applications of chemical physics. The Journal also publishes brief Communications of significant new findings, Perspectives on the latest advances in the field, and Special Topic issues. The Journal focuses on innovative research in experimental and theoretical areas of chemical physics, including spectroscopy, dynamics, kinetics, statistical mechanics, and quantum mechanics. In addition, topical areas such as polymers, soft matter, materials, surfaces/interfaces, and systems of biological relevance are of increasing importance. Topical coverage includes: Theoretical Methods and Algorithms Advanced Experimental Techniques Atoms, Molecules, and Clusters Liquids, Glasses, and Crystals Surfaces, Interfaces, and Materials Polymers and Soft Matter Biological Molecules and Networks.
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