Energetics and mechanism of the normal-to-amyloidogenic isomerization of β2-microglobulin: on-the-fly string method calculations.
Energetics and mechanism of the normal-to-amyloidogenic isomerization of β2-microglobulin: on-the-fly string method calculations.
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β2 微球蛋白正常至淀粉样蛋白异构化的能量学和机制：即时串法计算。
DOI：
10.1021/jp304805v
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Abrams,CameronF
中科院分区：
文献类型：
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作者：
Stober,SpencerT;Abrams,CameronF
我们使用集合变量中的动态有限温度弦方法来研究β-2-微球蛋白从正常构象到淀粉样变性构象的转变。我们表明，两个组氨酸残基的质子化状态是关键的，在酸性(质子化)条件下，N末端残基的置换破坏疏水口袋和侧链/侧链的静电吸引促进了向淀粉样蛋白形式的转变，这两者都促进了顺-反丙基异构化。在中性和质子化的情况下，正常到淀粉样蛋白异构化的自由能垒分别为14.9和7.1千卡/摩尔，这与在体外和血液透析相关的淀粉样变性中观察到的低pH条件下增强的淀粉样蛋白生成一致，并略低于实验确定的裸Pro-C异构化的势垒。我们建议进行特定的诱变实验，以进一步验证所观察到的机制。
We use on-the-fly finite temperature string method in collective variables to study the transition from a normal to an amyloidogenic conformation of β2-microglobulin. We show that the protonation state of two histidine residues is of key importance and that under acidic (protonating) conditions, the transition to the amyloidgenic form is facilitated by both displacement of N-terminal residues to disrupt a hydrophobic pocket and by side-chain/side-chain electrostatic attraction, both of which facilitate a cis–trans prolyl isomerization. The free energy barriers for the normal-to-amyloidogenic isomerization are found to be 14.9 and 7.1 kcal/mol for the neutral and protonated cases, respectively, consistent with enhanced amyloidgenesis at low pH observed both in vitro and in hemodialysis-associated amyloidosis, and somewhat lower than experimentally determined barriers for bare prolyl cis–trans isomerization. We suggest specific mutagenesis experiments which could be used to further validate the mechanism observed.