Center for Theoretical Biological Physics , Rice University , Houston , Texas 77005 , United States.
Department of Bioengineering , Rice University , Houston , Texas 77005 , United States.
J Phys Chem B. 2018 Dec 13;122(49):11414-11430. doi: 10.1021/acs.jpcb.8b07364. Epub 2018 Oct 1.
Many unrelated proteins and peptides have been found spontaneously to form amyloid fibers above a critical concentration. Even for a single sequence, however, the amyloid fold is not a single well-defined structure. Although the cross-β hydrogen bonding pattern is common to all amyloids, all other aspects of amyloid fiber structures are sensitive to both the sequence of the aggregating peptides and the solvent conditions under which the aggregation occurs. Amyloid fibers are easy to identify and grossly characterize using microscopy, but their insolubility and aperiodicity along the dimensions transverse to the fiber axis have complicated detailed experimental structural characterization. In this paper, we explore the landscape of possibilities for amyloid protofilament structures that are made up of a single stack of peptides associated in a parallel in-register manner. We view this landscape as a two-dimensional version of the usual three-dimensional protein folding problem: the survey of the two-dimensional folds of protein ribbons. Adopting this view leads to a practical method of predicting stable protofilament structures of arbitrary sequences. We apply this scheme to variants of Aβ, the amyloid forming peptide that is characteristically associated with Alzheimer's disease. Consistent with what is known from experiment, we find that Aβ protofibrils are polymorphic. To our surprise, however, the ribbon-folding landscape of Aβ turned out to be strikingly simple. We confirm that, at the level of the monomeric protofilament, the landscape for the Aβ sequence is reasonably well funneled toward structures that are similar to those that have been determined by experiment. The landscape has more distinct minima than does a typical globular protein landscape but fewer and deeper minima than the landscape of a randomly shuffled sequence having the same overall composition. It is tempting to consider the possibility that the significant degree of funneling of Aβ's ribbon-folding landscape has arisen as a result of natural selection. More likely, however, the intermediate complexity of Aβ's ribbon-folding landscape has come from the post facto selection of the Aβ sequence as an object of study by researchers because only by having a landscape with some degree of funneling can ordered aggregation of such a peptide occur at in vivo concentrations. In addition to predicting polymorph structures, we show that predicted solubilities of polymorphs correlate with experiment and with their elongation free energies computed by coarse-grained molecular dynamics.
许多不相关的蛋白质和肽已被发现，在超过临界浓度时会自发形成淀粉样纤维。然而，即使对于单一序列，淀粉样折叠也不是一种单一的明确结构。尽管所有淀粉样纤维都具有共同的交叉β氢键模式，但淀粉样纤维结构的所有其他方面都对聚集肽的序列和聚集发生时的溶剂条件敏感。使用显微镜很容易识别和大致描述淀粉样纤维，但由于其在纤维轴横向上的不溶性和非周期性，详细的实验结构特征变得复杂。在本文中，我们探索了由单个肽堆叠以平行、有序方式结合而成的淀粉样原纤维结构的可能性景观。我们将此景观视为通常的三维蛋白质折叠问题的二维版本：蛋白质带状物的二维折叠调查。采用这种观点，可以得到一种预测任意序列稳定原纤维结构的实用方法。我们将该方案应用于 Aβ 的变体，即与阿尔茨海默病有关的淀粉样形成肽。与实验结果一致，我们发现 Aβ 原纤维是多态的。令我们惊讶的是，然而，Aβ 的带状折叠景观却非常简单。我们证实，在单体原纤维水平上，Aβ 序列的景观在结构上与实验确定的结构非常相似。与典型的球状蛋白质景观相比，该景观具有更多的明显极小值，但与具有相同整体组成的随机打乱序列的景观相比，极小值更少且更深。考虑到 Aβ 带状折叠景观的显著程度可能是自然选择的结果，这是很诱人的。然而，更有可能的是，Aβ 带状折叠景观的中间复杂性来自于 Aβ 序列作为研究对象的事后选择，因为只有在具有一定程度的漏斗的情况下，这种肽才能在体内浓度下发生有序聚集。除了预测多态结构外，我们还表明，多态体的预测溶解度与实验以及通过粗粒分子动力学计算的其伸长自由能相关。
