Interaction of amyloid inhibitor proteins with amyloid beta peptides: insight from molecular dynamics simulations.
Interaction of amyloid inhibitor proteins with amyloid beta peptides: insight from molecular dynamics simulations.
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DOI：
10.1371/journal.pone.0113041
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Belfort G
中科院分区：
文献类型：
--
作者：
Das P;Kang SG;Temple S;Belfort G
了解蛋白质如人αB-晶状体蛋白和人溶菌酶抑制淀粉样β（Aβ）肽聚集的详细机制对于设计阿尔茨海默病的治疗是至关重要的。因此，在明确的溶剂中进行了无约束的原子分子动力学模拟，以表征α B-晶体蛋白核心结构域和溶菌酶存在下的Aβ17-42组装。模拟结果表明，这两种抑制剂蛋白竞争肽间的相互作用，结合的肽在早期阶段的聚集，这是一致的，在实验中报道的抑制作用。然而，每种抑制剂的Aβ结合动力学似乎不同。晶体蛋白和肽单体之间的结合，占主导地位的静电，是相对较弱的和短暂的，由于异构体的氨基酸分布的抑制剂表面。堆叠结合的Aβ寡聚体的寿命相对较长，因为它们与抑制剂蛋白形成更广泛的接触表面。相反，来自溶菌酶的高局部密度的精氨酸允许与Aβ肽单体的强结合，从而产生稳定的复合物。我们的研究结果不仅从原子细节上阐明了人α B-晶状体蛋白（一种天然伴侣蛋白）抑制淀粉样蛋白的机制与人溶菌酶的不同，而且可能有助于从头设计淀粉样蛋白抑制剂。
Knowledge of the detailed mechanism by which proteins such as human αB- crystallin and human lysozyme inhibit amyloid beta (Aβ) peptide aggregation is crucial for designing treatment for Alzheimer's disease. Thus, unconstrained, atomistic molecular dynamics simulations in explicit solvent have been performed to characterize the Aβ17–42 assembly in presence of the αB-crystallin core domain and of lysozyme. Simulations reveal that both inhibitor proteins compete with inter-peptide interaction by binding to the peptides during the early stage of aggregation, which is consistent with their inhibitory action reported in experiments. However, the Aβ binding dynamics appear different for each inhibitor. The binding between crystallin and the peptide monomer, dominated by electrostatics, is relatively weak and transient due to the heterogeneous amino acid distribution of the inhibitor surface. The crystallin-bound Aβ oligomers are relatively long-lived, as they form more extensive contact surface with the inhibitor protein. In contrast, a high local density of arginines from lysozyme allows strong binding with Aβ peptide monomers, resulting in stable complexes. Our findings not only illustrate, in atomic detail, how the amyloid inhibitory mechanism of human αB-crystallin, a natural chaperone, is different from that of human lysozyme, but also may aid de novo design of amyloid inhibitors.
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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：
5
作者：
Assarsson, Anna;Hellstrand, Erik;Linse, Sara
通讯作者：
Linse, Sara
DOI：
10.1073/pnas.1109526109
发表时间：
2012-02-14
影响因子：
11.1
作者：
Ahmad, Basir;Chen, Yujie;Lapidus, Lisa J.
通讯作者：
Lapidus, Lisa J.
影响因子：
13.8
作者：
Basha, Eman;O'Neill, Heather;Vierling, Elizabeth
通讯作者：
Vierling, Elizabeth
影响因子：
25
作者：
Cleary, JP;Walsh, DM;Ashe, KH
通讯作者：
Ashe, KH