Institute of Complex Systems: Structural Biochemistry, Research Centre Jülich, 52425 Jülich, Germany.
Proteins. 2013 Jul;81(7):1141-55. doi: 10.1002/prot.24263. Epub 2013 Apr 12.
Amyloid protein aggregation characterizes many neurodegenerative disorders, including Alzheimer's, Parkinson's, and Creutzfeldt-Jakob disease. Evidence suggests that amyloid aggregates may share similar aggregation pathways, implying simulation of full-length amyloid proteins is not necessary for understanding amyloid formation. In this study, we simulate GNNQQNY, the N-terminal prion-determining domain of the yeast protein Sup35 to investigate the thermodynamics of structural transitions during aggregation. Utilizing a coarse-grained model permits equilibration on relevant time scales. Replica-exchange molecular dynamics is used to gather simulation statistics at multiple temperatures and clear energy traps that would aversely impact results. Investigating the association of 3-, 6-, and 12-chain GNNQQNY systems by calculating thermodynamic quantities and orientational order parameters, we determine the aggregation pathway by studying aggregation states of GNNQQNY. We find that the aggregation of the hydrophilic GNNQQNY sequence is mainly driven by H-bond formation, leading to the formation of β-sheets from the very beginning of the assembly process. Condensation (aggregation) and ordering take place simultaneously, which is underpinned by the occurrence of a single heat capacity peak.
淀粉样蛋白聚集是许多神经退行性疾病的特征，包括阿尔茨海默病、帕金森病和克雅氏病。有证据表明，淀粉样聚集物可能具有相似的聚集途径，这意味着模拟全长淀粉样蛋白对于理解淀粉样形成并不必要。在这项研究中，我们模拟了酵母蛋白 Sup35 的 N 端朊病毒决定域 GNNQQNY，以研究在聚集过程中结构转变的热力学。利用粗粒度模型可以在相关时间尺度上进行平衡。复制交换分子动力学用于在多个温度下收集模拟统计数据，并消除可能对结果产生不利影响的能量陷阱。通过计算热力学量和取向有序参数来研究 3、6 和 12 链 GNNQQNY 系统的缔合，我们通过研究 GNNQQNY 的聚集状态来确定聚集途径。我们发现，亲水性 GNNQQNY 序列的聚集主要是由氢键形成驱动的，导致在组装过程的一开始就形成β-折叠。凝聚（聚集）和有序同时发生，这是由单个热容峰的出现所支撑的。
