Flöck Dagmar, Colacino Stefano, Colombo Giorgio, Di Nola Alfredo
Department of Chemistry, University of Rome La Sapienza, P.le Aldo Moro 5, Rome, Italy.
Proteins. 2006 Jan 1;62(1):183-92. doi: 10.1002/prot.20683.
Amyloid beta-proteins spontaneously aggregate and build plaques in the brains of Alzheimer's disease patients. The polypeptide has been the subject of extensive in vitro and computational research. Still, the pathway to aggregational forms and their exact conformations remain largely unclear. Here we present an extensive molecular dynamics approach simulating the protein in various temperatures, pH conditions, and with different charge states of the N- and C-termini, thus exploring the conformational space of the protein at large. Our results show that the protein is able to sample different conformations, many of which are rich in beta structure content, and all characterized by a rapid loss of helix 1 that converts into a pi-helix, while helix 2 samples random and beta-rich structures. Moreover, a hydrophobic cluster is observed involving Val18, Phe19, Ala21, and Gly25. The results are carefully compared with recent NMR and spectroscopic data, and are in global agreement with the experimental findings.
β-淀粉样蛋白在阿尔茨海默病患者大脑中会自发聚集并形成斑块。这种多肽一直是广泛的体外和计算研究的对象。然而，其聚集形式的途径及其确切构象在很大程度上仍不清楚。在此，我们提出一种广泛的分子动力学方法，在不同温度、pH条件下以及N端和C端具有不同电荷状态的情况下模拟该蛋白质，从而全面探索该蛋白质的构象空间。我们的结果表明，该蛋白质能够呈现不同的构象，其中许多富含β结构，其特征均为螺旋1迅速丧失并转变为π螺旋，而螺旋2呈现随机且富含β结构的构象。此外，观察到一个由Val18、Phe19、Ala21和Gly25组成的疏水簇。我们将结果与最近的核磁共振和光谱数据进行了仔细比较，总体上与实验结果一致。
