Folding events in the 21-30 region of amyloid-β-protein (Aβ) studied in silico
Folding events in the 21-30 region of amyloid-β-protein (Aβ) studied in silico
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DOI：
10.1073/pnas.0502006102
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发表时间：
2005-04-26
影响因子：
11.1
通讯作者：
Stanley, HE
中科院分区：
文献类型：
--
作者：
Borreguero, JM;Urbanc, B;Stanley, HE
淀粉样β蛋白（A β）的寡聚体组装与阿尔茨海默病的发病机制有关，是神经毒性的主要来源。最近的体外研究表明，10个残基片段，Ala-21-Ala-30，形成了全长a β折叠的成核结构。为了深入了解a β(21-30)折叠的机理，我们使用离散分子动力学算法和包含隐式溶剂和可变静电相互作用强度（EIS）的联合原子模型模拟了a β(21-30)折叠。我们发现A β(21-30)在Val-24和Lys-28侧链的丁基部分之间的有效疏水吸引力驱动下折叠成环状构象。在中等EIS [1.5 kcal/mol (1 cal = 4.18 J)]下，未展开的构象几乎消失，与实验观察一致。在最佳折叠条件下，Glu-22和Asp-23与Lys-28形成瞬态静电相互作用（EI），稳定环路构象。Glu-22-Lys-28是最有利的相互作用。高EIS，因为它发生在蛋白质和聚集体的内部，破坏了Val-24和Lys-28的包装。对未包装结构的分析显示，强El与Asp-23-Lys-28相互作用的优势，与全长A β原纤维的分子模型研究一致。涉及Lys-28的El的二元性质为Glu-22的氨基酸取代与阿尔茨海默病和脑淀粉样血管病的联系提供了机制解释。取代可能改变Glu-22或Asp-23参与接触形成的频率，并影响在A β(21-30)区形成的折叠核的稳定性。
Oligomeric assemblies of the amyloid beta-protein (A beta) have been implicated in the pathogenesis of Alzheimer's disease as a primary source of neurotoxicity. Recent in vitro studies have suggested that a 10-residue segment, Ala-21-Ala-30, forms a turn-like structure that nucleates the folding of the full-length A beta. To gain a mechanistic insight, we simulated A beta(21-30) folding by using a discrete molecular dynamics algorithm and a united-atom model incorporating implicit solvent and a variable electrostatic interaction strength (EIS). We found that A beta(21-30) folds into a loop-like conformation driven by an effective hydrophobic attraction between Val-24 and the butyl portion of the Lys-28 side chain. At medium EIS [1.5 kcal/mol (1 cal = 4.18 J)], unfolded conformations almost disappear, in agreement with experimental observations. Under optimal conditions for folding, Glu-22 and Asp-23 form transient electrostatic interactions (EI) with Lys-28 that stabilize the loop conformations. Glu-22-Lys-28 is the most favored interaction. High EIS, as it occurs in the interior of proteins and aggregates, destabilizes the packing of Val-24 and Lys-28. Analysis of the unpacked structures reveals strong El with predominance of the Asp-23-Lys-28 interaction, in agreement with studies of molecular modeling of full-length A beta fibrils. The binary nature of the El involving Lys-28 provides a mechanistic explanation for the linkage of amino acid substitutions at Glu-22 with Alzheimer's disease and cerebral amyloid angiopathy. Substitutions may alter the frequency of Glu-22 or Asp-23 involvement in contact formation and affect the stability of the folding nucleus formed in the A beta(21-30) region.