Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106, USA.
Curr Opin Struct Biol. 2011 Apr;21(2):209-20. doi: 10.1016/j.sbi.2011.02.002. Epub 2011 Mar 1.
The aggregation of soluble proteins into fibrillar species is a complex process that spans many lengths and time scales, and that involves the formation of numerous on-pathway and off-pathway intermediate species. Despite this complexity, several elements underlying the aggregation process appear to be universal. The kinetics typically follows a nucleation-growth process, and proteins with very different sequences aggregate to form similar fibril structures, populating intermediates with sufficient structural similarity to bind to a common antibody. This review focuses on a computational approach that exploits the common features of aggregation to simplify or 'coarse-grain' the representation of the protein. We highlight recent developments in coarse-grained modeling and illustrate how these models have been able to shed new light into the mechanisms of protein aggregation and the nature of aggregation intermediates. The roles of aggregation prone conformations in the monomeric state and the influence of inherent β-sheet and aggregation propensities in modulating aggregation pathways are discussed.
可溶性蛋白质聚集成纤维状物种是一个复杂的过程，跨越了许多长度和时间尺度，涉及到许多途径内和途径外中间物种的形成。尽管如此，聚合过程的几个基本要素似乎是普遍存在的。动力学通常遵循成核-生长过程，并且具有非常不同序列的蛋白质聚集形成相似的纤维结构，填充具有足够结构相似性以结合共同抗体的中间物。本综述重点介绍了一种利用聚合的共同特征来简化或“粗粒化”蛋白质表示的计算方法。我们强调了粗粒化建模的最新进展，并说明了这些模型如何能够揭示蛋白质聚集的机制和聚集中间物的性质。讨论了单体状态下易聚集构象的作用以及固有β-折叠和聚集倾向在调节聚集途径中的影响。
