Effects of Protein Crowders and Charge on the Folding of Superoxide Dismutase 1 Variants: A Computational Study
Effects of Protein Crowders and Charge on the Folding of Superoxide Dismutase 1 Variants: A Computational Study
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DOI：
10.1021/acs.jpcb.2c00819
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发表时间：
2022-06-10
影响因子：
3.3
通讯作者：
Morrison，Greg
中科院分区：
文献类型：
--
作者：
Sarkar，Atrayee;Gasic，Andrei G.;Morrison，Greg
神经退行性疾病肌萎缩侧索硬化症（ALS）与金属酶蛋白超氧化物歧化酶1（SOD 1）的错误折叠和聚集有关，通过突变使单体-二聚体界面不稳定。在细胞环境中，拥挤和静电屏蔽在SOD 1单体的折叠和聚集中起重要作用。尽管有许多关于突变对SOD 1折叠的影响的研究，但仍然缺乏对体内拥挤、折叠和聚集之间相互作用的清楚理解。使用基于结构的最小模型的分子动力学模拟，我们调查的作用，自我拥挤和电荷的折叠稳定性的SOD 1和G41 D突变体的实验人员感兴趣的折叠机制的改变，由一个单点突变从甘氨酸带电的天冬氨酸。我们表明，未折叠的SOD 1配置受到电荷和拥挤的显着影响，这一发现在全原子模拟中实现的成本极其高昂，而原生状态没有显着改变。残基41处的突变改变了未折叠状态下蛋白质之间的相互作用，而不是蛋白质内的相互作用。这篇论文表明静电可能在SOD 1的折叠途径中起重要作用，通过突变和离子浓度改变电荷可能会改变蛋白质之间的主导相互作用，对突变体的聚集有潜在的影响。这项工作为未折叠状态的改变提供了一个合理的原因，以解决为什么突变体G41 D引起了实验学家的兴趣，改变了SOD 1的折叠机制。
The neurodegenerative disease amyotrophic lateral sclerosis (ALS) is associated with the misfolding and aggregation of the metalloenzyme protein superoxide dismutase 1 (SOD1) via mutations that destabilize the monomer–dimer interface. In a cellular environment, crowding and electrostatic screening play essential roles in the folding and aggregation of the SOD1 monomers. Despite numerous studies on the effects of mutations on SOD1 folding, a clear understanding of the interplay between crowding, folding, and aggregation in vivo remains lacking. Using a structure-based minimal model for molecular dynamics simulations, we investigate the role of self-crowding and charge on the folding stability of SOD1 and the G41D mutant where experimentalists were intrigued by an alteration of the folding mechanism by a single point mutation from glycine to charged aspartic acid. We show that unfolded SOD1 configurations are significantly affected by charge and crowding, a finding that would be extremely costly to achieve with all-atom simulations, while the native state is not significantly altered. The mutation at residue 41 alters the interactions between proteins in the unfolded states instead of those within a protein. This paper suggests electrostatics may play an important role in the folding pathway of SOD1 and modifying the charge via mutation and ion concentration may change the dominant interactions between proteins, with potential impacts for aggregation of the mutants. This work provides a plausible reason for the alteration of the unfolded states to address why the mutant G41D causes the changes to the folding mechanism of SOD1 that have intrigued experimentalists.