Ikebe Jinzen, Kamiya Narutoshi, Ito Jun-Ichi, Shindo Heisaburo, Higo Junichi
School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
Protein Sci. 2007 Aug;16(8):1596-608. doi: 10.1110/ps.062721907.
The monomeric Alzheimer's beta amyloid peptide, Abeta, is known to adopt a disordered state in water at room temperature, and a circular dichroism (CD) spectroscopy experiment has provided the secondary-structure contents for the disordered state: 70% random, 25% beta-structural, and 5% helical. We performed an enhanced conformational sampling (multicanonical molecular dynamics simulation) of a 25-residue segment (residues 12-36) of Abeta in explicit water and obtained the conformational ensemble over a wide temperature range. The secondary-structure contents calculated from the conformational ensemble at 300 degrees K reproduced the experimental secondary-structure contents. The constructed free-energy landscape at 300 degrees K was not plain but rugged with five clearly distinguishable clusters, and each cluster had its own characteristic tertiary structure: a helix-structural cluster, two beta-structural clusters, and two random-structural clusters. This indicates that the contribution from the five individual clusters determines the secondary-structure contents experimentally measured. The helical cluster had a similarity with a stable helical structure for monomeric Abeta in 2,2,2-trifluoroethanol (TFE)/water determined by an NMR experiment: The positions of helices in the helical cluster were the same as those in the NMR structure, and the residue-residue contact patterns were also similar with those of the NMR structure. The cluster-cluster separation in the conformational space indicates that free-energy barriers separate the clusters at 300 degrees K. The two beta-structural clusters were characterized by different strand-strand hydrogen-bond (H-bond) patterns, suggesting that the free-energy barrier between the two clusters is due to the H-bond rearrangements.
已知单体阿尔茨海默病β淀粉样肽（Aβ）在室温下于水中呈无序状态，圆二色性（CD）光谱实验给出了该无序状态的二级结构含量：70%为无规结构、25%为β结构、5%为螺旋结构。我们在显式水环境中对Aβ的一个25个残基片段（残基12 - 36）进行了增强构象采样（多正则分子动力学模拟），并在较宽温度范围内获得了构象系综。从300 K时的构象系综计算得到的二级结构含量重现了实验二级结构含量。在300 K构建的自由能景观并非平坦，而是崎岖不平，有五个明显可区分的簇，每个簇都有其独特的三级结构：一个螺旋结构簇、两个β结构簇和两个无规结构簇。这表明这五个单独簇的贡献决定了实验测量的二级结构含量。螺旋簇与通过核磁共振实验确定的2,2,2 - 三氟乙醇（TFE）/水中单体Aβ的稳定螺旋结构相似：螺旋簇中螺旋的位置与核磁共振结构中的相同，残基 - 残基接触模式也与核磁共振结构相似。构象空间中的簇间分离表明在300 K时自由能垒将簇分隔开。两个β结构簇具有不同的链间氢键（H键）模式，这表明两个簇之间的自由能垒是由于H键重排所致。
