Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
Int J Mol Sci. 2023 Jun 25;24(13):10613. doi: 10.3390/ijms241310613.
Amyloid formation is a hallmark of various neurodegenerative disorders. In this contribution, energy landscapes are explored for various hexapeptides that are known to form amyloids. Heat capacity (CV) analysis at low temperature for these hexapeptides reveals that the low energy structures contributing to the first heat capacity feature above a threshold temperature exhibit a variety of backbone conformations for amyloid-forming monomers. The corresponding control sequences do not exhibit such structural polymorphism, as diagnosed via end-to-end distance and a dihedral angle defined for the monomer. A similar heat capacity analysis for dimer conformations obtained using basin-hopping global optimisation shows clear features in end-to-end distance versus dihedral correlation plots, where amyloid-forming sequences exhibit a preference for larger end-to-end distances and larger positive dihedrals. These results hold true for sequences taken from tau, amylin, insulin A chain, a de novo designed peptide, and various control sequences. While there is a little overall correlation between the aggregation propensity and the temperature at which the low-temperature CV feature occurs, further analysis suggests that the amyloid-forming sequences exhibit the key CV feature at a lower temperature compared to control sequences derived from the same protein.
淀粉样蛋白的形成是各种神经退行性疾病的一个标志。在本研究中，我们探索了各种已知形成淀粉样蛋白的六肽的能量景观。这些六肽的低温热容（CV）分析表明，在阈值温度以上贡献第一个 CV 特征的低能结构表现出淀粉样形成单体的各种骨架构象。相应的对照序列没有表现出这种结构多态性，这可以通过单体的末端到末端距离和二面角来诊断。使用 basin-hopping 全局优化方法对二聚体构象进行类似的热容分析，在末端到末端距离与二面角相关图中显示出明显的特征，其中淀粉样形成序列表现出对更大的末端到末端距离和更大的正值二面角的偏好。这些结果适用于取自 tau、淀粉样蛋白、胰岛素 A 链、从头设计的肽以及各种对照序列的序列。虽然聚集倾向与低温 CV 特征出现的温度之间存在一定的整体相关性，但进一步的分析表明，与同一蛋白质衍生的对照序列相比，淀粉样形成序列在较低温度下表现出关键的 CV 特征。
