Center for Theoretical Biological Physics, Houston, Texas 77005, United States.
Department of Chemistry, Rice University, Houston, Texas 77005, United States.
J Phys Chem B. 2022 Jul 21;126(28):5250-5261. doi: 10.1021/acs.jpcb.2c03676. Epub 2022 Jul 10.
The abnormal aggregation of α-synulcein is associated with multiple neurodegenerative diseases such as Parkinson's disease. The hydrophobic non-amyloid component (NAC) region of α-synuclein comprises the core of the fibril in vitro and in vivo. In this work, we study the aggregation landscape of the hydrophobic NAC region of α-synuclein using a transferrable coarse-grained force field, the associative memory water-mediated structure, and energy model (AWSEM). Using structural similarity, we can group metastable states on the free energy landscape of aggregation into three types of oligomers: disordered oligomers, prefibrillar oligomers with disordered tips, and ordered prefibrillar oligomers. The prefibrillar oligomers with disordered tips have more in-register parallel β strands than do the fully disordered oligomers but have fewer in-register parallel β strands than the ordered prefibrillar oligomers. Along with the ordered prefibrillar species, the disordered oligomeric states dominate at small oligomer sizes while the prefibrillar species with disordered tips thermodynamically dominate with the growth of oligomers. The topology of the aggregation landscape and observations in simulations suggest there is backtracking between ordered prefibrillar oligomers and other kinds of oligomers as the aggregation proceeds. The significant structural differences between the ordered prefibrillar oligomers and the disordered oligomers support the idea that the growth of these two kinds of oligomers involves kinetically independent parallel pathways. In contrast, the overall structural similarity between the fully ordered prefibrillar oligomers and the prefibrillar oligomers with disordered tips implies that two channels can interconvert on slower time scales. We also evaluate the effects of phosphorylation on the aggregation free energy landscape using statistical mechanical perturbation theory.
α-突触核蛋白的异常聚集与多种神经退行性疾病有关，如帕金森病。α-突触核蛋白的疏水性非淀粉样成分（NAC）区域构成了体外和体内纤维的核心。在这项工作中，我们使用可转移的粗粒力场、关联记忆水介导的结构和能量模型（AWSEM）研究了α-突触核蛋白疏水性 NAC 区域的聚集景观。通过结构相似性，我们可以将聚集自由能景观中的亚稳态分为三种类型的低聚物：无规低聚物、无序尖端的原纤维前低聚物和有序原纤维前低聚物。无序尖端的原纤维前低聚物具有比完全无序的低聚物更多的规则平行β链，但比有序的原纤维前低聚物具有更少的规则平行β链。与有序的原纤维前低聚物一样，无序的低聚物状态在小低聚物尺寸时占主导地位，而无序尖端的原纤维物种在低聚物的生长过程中在热力学上占主导地位。聚集景观的拓扑结构和模拟中的观察结果表明，随着聚集的进行，有序的原纤维前低聚物和其他类型的低聚物之间存在回溯。有序的原纤维前低聚物和无规低聚物之间的显著结构差异支持这样一种观点，即这两种低聚物的生长涉及动力学独立的平行途径。相比之下，完全有序的原纤维前低聚物和无序尖端的原纤维前低聚物之间的整体结构相似性意味着两个通道可以在较慢的时间尺度上相互转换。我们还使用统计力学微扰理论评估了磷酸化对聚集自由能景观的影响。
