Daidone Isabella, Simona Fabio, Roccatano Danilo, Broglia Ricardo A, Tiana Guido, Colombo Giorgio, Di Nola Alfredo
Department of Chemistry, University of Rome La Sapienza, Rome, Italy.
Proteins. 2004 Oct 1;57(1):198-204. doi: 10.1002/prot.20178.
Understanding the conformational transitions that trigger the aggregation and amyloidogenesis of otherwise soluble peptides at atomic resolution is of fundamental relevance for the design of effective therapeutic agents against amyloid-related disorders. In the present study the transition from ideal alpha-helical to beta-hairpin conformations is revealed by long timescale molecular dynamics simulations in explicit water solvent, for two well-known amyloidogenic peptides: the H1 peptide from prion protein and the Abeta(12-28) fragment from the Abeta(1-42) peptide responsible for Alzheimer's disease. The simulations highlight the unfolding of alpha-helices, followed by the formation of bent conformations and a final convergence to ordered in register beta-hairpin conformations. The beta-hairpins observed, despite different sequences, exhibit a common dynamic behavior and the presence of a peculiar pattern of the hydrophobic side-chains, in particular in the region of the turns. These observations hint at a possible common aggregation mechanism for the onset of different amyloid diseases and a common mechanism in the transition to the beta-hairpin structures. Furthermore the simulations presented herein evidence the stabilization of the alpha-helical conformations induced by the presence of an organic fluorinated cosolvent. The results of MD simulation in 2,2,2-trifluoroethanol (TFE)/water mixture provide further evidence that the peptide coating effect of TFE molecules is responsible for the stabilization of the soluble helical conformation.
在原子分辨率下理解触发原本可溶肽聚集和淀粉样变的构象转变，对于设计针对淀粉样相关疾病的有效治疗药物至关重要。在本研究中，通过在明确的水溶剂中进行长时间尺度的分子动力学模拟，揭示了两种著名的淀粉样生成肽从理想的α-螺旋构象到β-发夹构象的转变：来自朊病毒蛋白的H1肽和来自导致阿尔茨海默病的Aβ(1-42)肽的Aβ(12-28)片段。模拟突出了α-螺旋的展开，随后形成弯曲构象，最终收敛到有序的对齐β-发夹构象。观察到的β-发夹尽管序列不同，但表现出共同的动态行为，并且存在疏水侧链的特殊模式，特别是在转角区域。这些观察结果暗示了不同淀粉样疾病发病可能存在共同的聚集机制，以及向β-发夹结构转变的共同机制。此外，本文所呈现的模拟证明了有机氟化共溶剂的存在诱导的α-螺旋构象的稳定性。在2,2,2-三氟乙醇（TFE）/水混合物中的分子动力学模拟结果进一步证明，TFE分子的肽包被效应负责可溶性螺旋构象的稳定。
