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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：蛋白质Cu中的突变和氧化改性，Zn超氧化物歧化酶（SOD1）涉及在肌营养的侧面硬化症（ALS）中的运动神经元死亡中，目前无法治愈的，致命的神经变性疾病。在这里，我们采用了隐含溶剂中的引导，全原子分子动力学模拟，以研究突变或翻译后修饰（PTMS）对SOD1对金属亲和力，二聚体稳定性和机械磁性的显着性。作为序列指数的函数诱导适度结构变形所需的作品构成了天然盆地中的结构刚性的“机械指纹”，我们能够从PTM变体中明确地区分野生型SOD1并测量给定的野生型SOD1 PTM结构完整性。工作价值的累积分布提供了一种干净地区分SOD1变体的方法。二硫化物减少使二聚体稳定性变得不如除去任何金属的去除，但不是除去两个金属。有趣的是，我们发现二硫化物降低机械稳定APO-SOD1单体，强调天然盆地机械性能和平衡热力学稳定性之间的差异，并阐明了APO状态的内应力的存在。研究的所有PTM和ALS相关突变体显示出丢失Cu或Zn的倾向增加，并在ALS的进展中致为至关重要的单体化方法。 Cu的价强烈调节其具有束缚的自由能。同样，多个突变体比SOD1的二硫化或APO形式更容易丧失金属和单体化。需要距离约束来计算使用热力学循环验证的金属粘合和二聚体分离的自由能量。当移除距离约束时，结果同意从jarzynski平等的直接应用获得的结果。 ？2013年elestvier有限公司保留所有权利。

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