Amyloid beta-protein monomer folding: free-energy surfaces reveal alloform-specific differences.
Amyloid beta-protein monomer folding: free-energy surfaces reveal alloform-specific differences.
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DOI：
10.1016/j.jmb.2008.09.039
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发表时间：
2008-12-12
影响因子：
5.6
通讯作者：
Teplow, David B.
中科院分区：
文献类型：
--
作者：
Yang, Mingfeng;Teplow, David B.
Aβ40 和 Aβ42 之间结构动力学的同种异型特异性差异似乎是阿尔茨海默病发病机制的基础。为了阐明这些差异，我们进行了 µs 时间尺度的复制品交换分子动力学模拟，对 Aβ 单体的构象空间进行采样，并构建了其自由能表面。我们发现这两种肽单体都不是非结构化的，而是每个肽单体都可以被描述为一个独特的统计卷曲，其中存在五个相对独立的折叠单元，包括残基1-5、10-13、17-22、28-37和39-42，它们通过四个转角结构连接。两种肽的自由能表面的特征是两个大盆，包含具有大量 α 螺旋或 β 折叠含量的构象异构体。这些盆地内部和之间的构象转变非常迅速。 Aβ42 C 末端的两个额外疏水残基 Ile41 和 Ala42 显着增加了 C 末端内以及 C 末端与中央疏水簇 (Leu17-Ala21) 之间的接触。结果，Aβ42的β结构比Aβ40更稳定，并且Aβ42中的构象平衡向β结构移动。这些结果表明，稳定 α-螺旋 Aβ 构象异构体（或破坏 β-折叠状态）的药物将阻止神经毒性寡聚物的形成。我们的模拟中确定的原子分辨率构象异构体结构可以作为此目的的有用目标。构象异构体还为模拟 Aβ 寡聚化提供了起点，这一过程被认为是 AD 的关键致病事件。
Alloform-specific differences in structural dynamics between Aβ40 and Aβ42 appear to underlie the pathogenesis of Alzheimer’s disease. To elucidate these differences, we performed µs time-scale replica exchange molecular dynamics simulations to sample the conformational space of the Aβ monomer and constructed its free energy surface. We find that neither peptide monomer is unstructured, but rather that each may be described as a unique statistical coil in which five relatively independent folding units exist, comprising residues 1–5, 10–13, 17–22, 28–37, and 39–42, which are connected by four turn structures. The free energy surfaces of both peptides are characterized by two large basins, comprising conformers either with substantial α-helix or β-sheet content. Conformational transitions within and between these basins are rapid. The two additional hydrophobic residues at the Aβ42 C-terminus, Ile41 and Ala42, significantly increase contacts within the C-terminus and between the C-terminus and the central hydrophobic cluster (Leu17-Ala21). As a result, the β-structure of Aβ42 is more stable than that of Aβ40 and the conformational equilibrium in Aβ42 shifts towards β-structure. These results suggest that drugs stabilizing α-helical Aβ conformers (or destabilizing the β-sheet state) would block formation of neurotoxic oligomers. The atomic-resolution conformer structures determined in our simulations may serve as useful targets for this purpose. The conformers also provide starting points for simulations of Aβ oligomerization, a process postulated to be the key pathogenetic event in AD.
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DOI：
10.1073/pnas.0502006102
发表时间：
2005-04-26
影响因子：
11.1
作者：
Borreguero, JM;Urbanc, B;Stanley, HE
通讯作者：
Stanley, HE
DOI：
10.1002/prot.340110305
发表时间：
1991-01-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
ICHIYE, T;KARPLUS, M
通讯作者：
KARPLUS, M
DOI：
10.1002/prot.340230412
发表时间：
1995-12-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
Frishman, D;Argos, P
通讯作者：
Argos, P
影响因子：
64.8
作者：
Ashworth, Justin;Havranek, James J.;Baker, David
通讯作者：
Baker, David
DOI：
10.1073/pnas.0404236101
发表时间：
2004-08-24
影响因子：
11.1
作者：
Fitzkee, NC;Rose, GD
通讯作者：
Rose, GD