Abstract:
The aggregation of transactive response deoxyribonucleic acid (DNA) binding protein of 43 kDa (TDP-43) into ubiquitin-positive inclusions is closely associated with amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and chronic traumatic encephalopathy. The 370-375 fragment of TDP-43 (370GNNSYS375, TDP-43370-375), the amyloidogenic hexapeptides, can be prone to forming pathogenic amyloid fibrils with the characteristic of steric zippers. Previous experiments reported the ALS-associated mutation, serine 375 substituted by glycine (S375G) is linked to early onset disease and protein aggregation of TDP-43. Based on this, it is necessary to explore the underlying molecular mechanisms. By utilizing all-atom molecular dynamics (MD) simulations of 102 μs in total, we investigated the impact of S375G mutation on the conformational ensembles and oligomerization dynamics of TDP-43370-375 peptides. Our replica exchange MD simulations show that S375G mutation could promote the unstructured conformation formation and induce peptides to form a loose packed oligomer, thus inhibiting the aggregation of TDP-43370-375. Further analyses suggest that S375G mutation displays a reduction effect on the number of total hydrogen bonds and contacts among TDP-43370-375 peptides. Hydrogen bonding and polar interactions among TDP-43370-375 peptides, as well as Y374-Y374 π-π stacking interaction, are attenuated by S375G mutation. Additional microsecond MD simulations demonstrate that S375G mutation could prohibit the conformational conversion to β-structure-rich aggregates and possess an inhibitory effect on the oligomerization dynamics of TDP-43370-375. This study offers for the first time of molecular insights into the S375G mutation affecting the aggregation of TDP-43370-375 at the atomic level, and may open new avenues in the development of future site-specific mutation therapeutics.
摘要:
43kDa的反应性脱氧核糖核酸(DNA)结合蛋白(TDP-43)聚集成泛素阳性包涵体与肌萎缩侧索硬化症(ALS)密切相关,额颞叶变性,慢性创伤性脑病.TDP-43的370-375片段(370GNNSYS375,TDP-43370-375),淀粉样六肽,可容易形成具有立体拉链特征的致病性淀粉样原纤维。以前的实验报道了与ALS相关的突变,被甘氨酸取代的丝氨酸375(S375G)与TDP-43的早发性疾病和蛋白质聚集有关。基于此,有必要探索潜在的分子机制。通过利用总共102μs的全原子分子动力学(MD)模拟,我们研究了S375G突变对TDP-43370-375肽构象集合和寡聚化动力学的影响。我们的副本交换MD模拟表明,S375G突变可以促进非结构化构象的形成,并诱导肽形成松散的寡聚体,从而抑制TDP-43370-375的聚集。进一步的分析表明,S375G突变对TDP-43370-375肽之间的总氢键和接触的数量显示出减少的作用。TDP-43370-375肽之间的氢键和极性相互作用,以及Y374-Y374π-π堆叠相互作用,通过S375G突变减弱。其他微秒MD模拟表明,S375G突变可以阻止构象转化为富含β结构的聚集体,并对TDP-43370-375的寡聚化动力学具有抑制作用。这项研究首次提供了对S375G突变在原子水平上影响TDP-43370-375聚集的分子见解,并可能为未来位点特异性突变疗法的发展开辟新的途径。