Schrodinger Inc., 120 West 45th Street New York, New York, 10036, NY, USA.
Baker Laboratory of Chemistry and Chemical Biology, Cornell University, Ithaca, 14853-1301, NY, USA.
Methods Mol Biol. 2022;2340:79-104. doi: 10.1007/978-1-0716-1546-1_5.
Protein aggregation is the cause of many, often lethal, diseases, including the Alzheimer's, Parkinson's, and Huntington's diseases, and familial amyloidosis. Theoretical investigation of the mechanism of this process, including the structures of the oligomeric intermediates which are the most toxic, is difficult because of long time scale of aggregation. Coarse-grained models, which enable us to extend the simulation time scale by three or more orders of magnitude, are, therefore, of great advantage in such studies. In this chapter, we describe the application of the physics-based UNited RESidue (UNRES) force field developed in our laboratory to study protein aggregation, in both free simulations and simulations of aggregation propagation from an existing template (seed), and illustrate it with the examples of Aβ-peptide aggregation and Aβ-peptide-assisted aggregation of the peptides derived from the repeat domains of tau (TauRD).
蛋白质聚集是许多疾病的原因，包括阿尔茨海默病、帕金森病、亨廷顿病和家族性淀粉样变性病等，这些疾病往往是致命的。由于聚集过程的时间尺度很长，因此对该过程的机制进行理论研究，包括最具毒性的低聚物中间体的结构，是很困难的。粗粒度模型通过将模拟时间尺度延长三个或更多数量级，因此在这些研究中具有很大的优势。在本章中，我们描述了我们实验室开发的基于物理的 UNited RESidue (UNRES)力场在自由模拟和从现有模板（种子）传播聚集的模拟中的应用，并通过 Aβ-肽聚集和 Aβ-肽辅助聚集的例子来说明，TauRD 重复域衍生的肽。
