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首页> 外文期刊>Journal of Molecular Biology >Mechanical probes of SOD1 predict systematic trends in metal and dimer affinity of ALS-associated mutants
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Mechanical probes of SOD1 predict systematic trends in metal and dimer affinity of ALS-associated mutants

机译：SOD1的机械探针可预测ALS相关突变体的金属和二聚体亲和力的系统趋势

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Mutations and oxidative modification in the protein Cu,Zn superoxide dismutase (SOD1) have been implicated in the death of motor neurons in amyotrophic lateral sclerosis (ALS), a presently incurable, invariably fatal neurodegenerative disease. Here we employ steered, all-atom molecular dynamics simulations in implicit solvent to investigate the significance of either mutations or post-translational modifications (PTMs) to SOD1 on metal affinity, dimer stability, and mechanical malleability. The work required to induce moderate structural deformations as a function of sequence index constitutes a "mechanical fingerprint" measuring structural rigidity in the native basin, from which we are able to unambiguously distinguish wild-type SOD1 from PTM variants and measure the severity of a given PTM on structural integrity. The cumulative distribution of work values provided a way to cleanly discriminate between SOD1 variants. Disulfide reduction destabilizes dimer stability more than the removal of either metal, but not moreso than the removal of both metals. Intriguingly, we found that disulfide reduction mechanically stabilizes apo-SOD1 monomer, underscoring the differences between native basin mechanical properties and equilibrium thermodynamic stabilities and elucidating the presence of internal stress in the apo state. All PTMs and ALS-associated mutants studied showed an increased tendency to lose either Cu or Zn and to monomerize - processes known to be critical in the progression of ALS. The valence of Cu strongly modulates its binding free energy. As well, several mutants were more susceptible to loss of metals and monomerization than the disulfide-reduced or apo forms of SOD1. Distance constraints are required to calculate free energies for metal binding and dimer separation, which are validated using thermodynamic cycles. When distance constraints are removed, the results agree with those obtained from direct application of the Jarzynski equality. ?2013 Elsevier Ltd. All rights reserved.
机译：铜，锌超氧化物歧化酶（SOD1）蛋白的突变和氧化修饰与肌萎缩性侧索硬化症（ALS）的运动神经元死亡有关，肌萎缩性侧索硬化症（ALS）是目前无法治愈的，致命性的神经退行性疾病。在这里，我们在隐性溶剂中采用受控的全原子分子动力学模拟，以研究突变或SOD1的翻译后修饰（PTM）对金属亲和力，二聚体稳定性和机械延展性的重要性。诱导适度结构变形作为序列指数的函数所需的工作构成了“机械指纹”，用于测量原生盆地中的结构刚度，从中我们可以明确区分野生型SOD1与PTM变体并测量给定强度PTM的结构完整性。工作值的累积分布提供了一种清晰地区分SOD1变体的方法。二硫化物的还原使二聚体的稳定性比除去任何一种金属更不稳定，但不超过除去两种金属。有趣的是，我们发现二硫化物还原可机械稳定apo-SOD1单体，强调了天然盆地力学性能和平衡热力学稳定性之间的差异，并阐明了apo状态下的内部应力。研究的所有PTM和与ALS相关的突变体均显示出丧失Cu或Zn以及单体化的趋势，这是已知的对ALS进展至关重要的过程。 Cu的价强烈地调节其结合自由能。同样，一些突变体比二硫化物还原或脱辅基形式的SOD1更容易丢失金属和单体化。计算金属结合和二聚体分离的自由能需要距离约束，这些约束使用热力学循环进行了验证。消除距离限制后，结果与直接应用Jarzynski等式所得的结果一致。 ？2013 Elsevier Ltd.保留所有权利。

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