Catalytic Mechanism of Amyloid-β Peptide Degradation by Insulin Degrading Enzyme: Insights from Quantum Mechanics and Molecular Mechanics Style Møller-Plesset Second Order Perturbation Theory Calculation.
Catalytic Mechanism of Amyloid-β Peptide Degradation by Insulin Degrading Enzyme: Insights from Quantum Mechanics and Molecular Mechanics Style Møller-Plesset Second Order Perturbation Theory Calculation.
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DOI：
10.1021/acs.jcim.8b00406
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发表时间：
2018-09-24
影响因子：
5.6
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Lai R;Tang WJ;Li H
胰岛素降解酶（IDE）是一种降解淀粉样蛋白-β (a β)肽和胰岛素的金属蛋白酶，与阿尔茨海默病和糖尿病有关。IDE催化的Aβ肽降解机制在阿尔茨海默病的治疗方法设计中具有重要意义，但目前尚未完全了解。本文采用量子力学和分子力学（QM/MM）相结合的Møller-Plesset二阶微扰理论（MP2）几何优化计算，探讨了人IDE对a - β40 Phe19-Phe20肽键裂解的催化机理。利用QM/MM MP2优化分析表明，在酶-底物（ES）复合物的活性位点存在一个中性水分子。水分子与IDE的阴离子Glu111形成氢键，但不直接与催化的Zn离子结合。QM/MM DFTB3分子动力学模拟证实了这一点。我们的研究还表明，IDE水解a - β40 Phe19-Phe20肽键包括四个关键步骤。中性水首先通过向锌离子移动并与之结合而被激活。活化的中性水分子攻击Phe19-Phe20肽键的C原子，形成宝石二醇中间体。其次是Phe19-Phe20肽键的N原子质子化，形成具有延长C-N键的中间体。最后一步是断开Phe19-Phe20的碳氮键。最后一步为速率决定步骤，计算得到的吉布斯自由活化能为17.34 kcal/mol，与实验值16.7 kcal/mol吻合较好。这一机制为设计生物化学方法来调节IDE在人体内的活性提供了基础。
Insulin degrading enzyme (IDE), a metalloprotease that degrades amyloid-β (Aβ) peptides and insulin, is associated with Alzheimer’s disease and diabetes. The mechanism of IDE catalyzed degrading of Aβ peptides, which is of fundamental importance in the design of therapeutic methods for Alzheimer’s disease, has not been fully understood. In this work, combined quantum mechanics and molecular mechanics (QM/MM) style Møller-Plesset second order perturbation theory (MP2) geometry optimization calculations are performed to investigate the catalytic mechanism of the Aβ40 Phe19-Phe20 peptide bond cleavage by human IDE. The analyses using QM/MM MP2 optimization suggest that a neutral water molecule is at the active site of the enzyme-substrate (ES) complex. The water molecule is in hydrogen bonding with the nearby anionic Glu111 of IDE, but not directly bound to the catalytic Zn ion. This is confirmed by QM/MM DFTB3 molecular dynamics simulation. Our studies also reveal that the hydrolysis of the Aβ40 Phe19-Phe20 peptide bond by IDE consists of four key steps. The neutral water is first activated by moving toward and binding to the Zn ion. A gem-diol intermediate is then formed by the activated neutral water molecule attacking the C atom of the Phe19-Phe20 peptide bond. The next is the protonation of the N atom of Phe19-Phe20 peptide bond to form an intermediate with an elongated C-N bond. The final step is the breaking of the Phe19-Phe20 C-N bond. The final step is the rate-determining step with a calculated Gibbs free energy of activation of 17.34 kcal/mol, in good agreement with the experimental value 16.7 kcal/mol. This mechanism provides the basis for the design of biochemical methods to modulate the activity of IDE in humans.
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小分子对胰岛素降解酶的催化位点诱导小鼠葡萄糖不耐症。
影响因子：
16.6
作者：
Deprez-Poulain R;Hennuyer N;Bosc D;Liang WG;Enée E;Marechal X;Charton J;Totobenazara J;Berte G;Jahklal J;Verdelet T;Dumont J;Dassonneville S;Woitrain E;Gauriot M;Paquet C;Duplan I;Hermant P;Cantrelle FX;Sevin E;Culot M;Landry V;Herledan A;Piveteau C;Lippens G;Leroux F;Tang WJ;van Endert P;Staels B;Deprez B
通讯作者：
Deprez B
影响因子：
6.7
作者：
Charton J;Gauriot M;Guo Q;Hennuyer N;Marechal X;Dumont J;Hamdane M;Pottiez V;Landry V;Sperandio O;Flipo M;Buee L;Staels B;Leroux F;Tang WJ;Deprez B;Deprez-Poulain R
通讯作者：
Deprez-Poulain R
影响因子：
3
作者：
Cieplak, P;Caldwell, J;Kollman, P
通讯作者：
Kollman, P
影响因子：
5.5
作者：
Gaus, Michael;Cui, Qiang;Elstner, Marcus
通讯作者：
Elstner, Marcus
DOI：
10.1073/pnas.0230450100
发表时间：
2003-04-01
影响因子：
11.1
作者：
Farris, W;Mansourian, S;Guénette, S
通讯作者：
Guénette, S