Michaels Thomas C T, Šarić Anđela, Habchi Johnny, Chia Sean, Meisl Georg, Vendruscolo Michele, Dobson Christopher M, Knowles Tuomas P J
Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; email:
Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA.
Annu Rev Phys Chem. 2018 Apr 20;69:273-298. doi: 10.1146/annurev-physchem-050317-021322. Epub 2018 Feb 28.
Understanding how normally soluble peptides and proteins aggregate to form amyloid fibrils is central to many areas of modern biomolecular science, ranging from the development of functional biomaterials to the design of rational therapeutic strategies against increasingly prevalent medical conditions such as Alzheimer's and Parkinson's diseases. As such, there is a great need to develop models to mechanistically describe how amyloid fibrils are formed from precursor peptides and proteins. Here we review and discuss how ideas and concepts from chemical reaction kinetics can help to achieve this objective. In particular, we show how a combination of theory, experiments, and computer simulations, based on chemical kinetics, provides a general formalism for uncovering, at the molecular level, the mechanistic steps that underlie the phenomenon of amyloid fibril formation.
理解正常可溶的肽和蛋白质如何聚集形成淀粉样纤维，是现代生物分子科学诸多领域的核心问题，涵盖从功能性生物材料的开发到针对诸如阿尔茨海默病和帕金森病等日益普遍的医学病症设计合理治疗策略等方面。因此，迫切需要开发模型来从机制上描述淀粉样纤维是如何由前体肽和蛋白质形成的。在此，我们回顾并讨论化学反应动力学中的观点和概念如何有助于实现这一目标。特别是，我们展示了基于化学动力学的理论、实验和计算机模拟相结合，如何提供一种通用形式，在分子水平上揭示淀粉样纤维形成现象背后的机制步骤。
