Emergence of Alternative Structures in Amyloid Beta 1-42 Monomeric Landscape by N-terminal Hexapeptide Amyloid Inhibitors
Emergence of Alternative Structures in Amyloid Beta 1-42 Monomeric Landscape by N-terminal Hexapeptide Amyloid Inhibitors
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DOI：
10.1038/s41598-017-10212-5
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发表时间：
2017-08-30
影响因子：
4.6
通讯作者：
Das, Payel
中科院分区：
文献类型：
--
作者：
Chakraborty, Srirupa;Das, Payel
阿尔茨海默病（AD）的特征在于淀粉样蛋白β（A β）肽沉积到脑中的老年斑中。虽然大多数家族性突变与早发性AD相关，但最近的研究报告了两种遗传性人类A β变体（即A2 T和A2 V）在杂合状态下的AD保护性质。还发现A2 V A β 1-6（A β（6））六肽和WT A β 1-42（A β（42））的混合物具有神经保护作用。受这些发现的启发，在这项研究中，我们研究了WT，A2 V和A2 T A β（6）六肽结合对单体WT A β（42）景观的影响。为此目的，我们进行了广泛的原子交换分子动力学模拟，阐明了与WT A β（6）相比，A β（42）与A2 V和A2 T六肽的优先结合。由于六肽缔合，揭示了A β（42）景观的显著重组，如通过降低中央和C-末端疏水斑块之间的瞬时相互作用所表现的。同时，A β 6结合的A β（42）单体表现出强烈依赖于六肽序列的替代结构特征。例如，中心螺旋更频繁地在A2 T结合的单体内聚集，而A2 V结合的A β（42）通常在整体病症中增强。总之，本模拟提供了新的分子见解的N-末端六肽结合的影响，A β（42）单体结构，这可能有助于解释其报告的淀粉样蛋白抑制性能。
Alzheimer's disease (AD) is characterized by deposition of amyloid beta (A beta) peptides into senile plaques in the brain. While most familial mutations are associated with early-onset AD, recent studies report the AD-protective nature of two genetic human A beta variants, i.e. A2T and A2V, in the heterozygous state. The mixture of A2V A beta 1-6 (A beta(6)) hexapeptide and WT A beta 1-42 (A beta(42)) is also found neuroprotective. Motivated by these findings, in this study we investigate the effects of WT, A2V, and A2T A beta(6) hexapeptide binding on the monomeric WT A beta(42) landscape. For this purpose, we have performed extensive atomistic Replica Exchange Molecular Dynamics simulations, elucidating preferential binding of A beta(42) with the A2V and A2T hexapeptides compared to WT A beta(6). A notable reorganization of the A beta(42) landscape is revealed due to hexapeptide association, as manifested by lowering of transient interactions between the central and C-terminal hydrophobic patches. Concurrently, A beta 6-bound A beta(42) monomer exhibits alternative structural features that are strongly dependent on the hexapeptide sequence. For example, a central helix is more frequently populated within the A2T-bound monomer, while A2V-bound A beta(42) is often enhanced in overall disorder. Taken together, the present simulations offer novel molecular insights onto the effect of the N-terminal hexapeptide binding on the A beta(42) monomer structure, which might help in explaining their reported amyloid inhibition properties.