Departamento de Física and BioISI - Biosystems and Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, CampoGrande, Ed. C8, 1749-016 Lisboa, Portugal.
Phys Biol. 2021 Jun 30;18(5). doi: 10.1088/1478-3975/ac08ec.
Protein beta-2-microglobulin (2m) is classically considered the causative agent of dialysis related amyloidosis, a conformational disorder that affects patients undergoing long-term hemodialysis. The wild type (WT) form, the Δ6 structural variant, and the D76N mutant have been extensively used as model systems of2m aggregation. In all of them, the native structure is stabilized by a disulfide bridge between the sulphur atoms of the cysteine residues 25 (at B strand) and 80 (at F strand), which has been considered fundamental in2m fibrillogenesis. Here, we use extensive discrete molecular dynamics simulations of a full atomistic structure-based model to explore the role of this disulfide bridge as a modulator of the folding space of2m. In particular, by considering different models for the disulfide bridge, we explore the thermodynamics of the folding transition, and the formation of intermediate states that may have the potential to trigger the aggregation cascade. Our results show that the dissulfide bridge affects folding transition and folding thermodynamics of the considered model systems, although to different extents. In particular, when the interaction between the sulphur atoms is stabilized relative to the other intramolecular interactions, or even locked (i.e. permanently established), the WT form populates an intermediate state featuring a well preserved core and two unstructured termini, which was previously detected only for the D76N mutant. The formation of this intermediate state may have important implications in our understanding of2m fibrillogenesis.
β2-微球蛋白（2m）被认为是透析相关淀粉样变的致病因子，这是一种构象疾病，影响长期接受血液透析的患者。野生型（WT）形式、Δ6 结构变体和 D76N 突变体已被广泛用作 2m 聚集的模型系统。在所有这些模型中，天然结构通过半胱氨酸残基 25（在 B 链）和 80（在 F 链）的硫原子之间的二硫键稳定，这被认为是 2m 原纤维形成的基础。在这里，我们使用广泛的离散分子动力学模拟全原子结构模型来探索该二硫键作为 2m 折叠空间调节剂的作用。特别是，通过考虑不同的二硫键模型，我们探索了折叠跃迁的热力学以及可能具有引发聚集级联潜力的中间状态的形成。我们的结果表明，二硫键影响所考虑的模型系统的折叠跃迁和折叠热力学，尽管程度不同。特别是，当硫原子之间的相互作用相对于其他分子内相互作用稳定，甚至锁定（即永久建立）时，WT 形式会进入一个中间状态，该状态具有保存完好的核心和两个无结构末端，这以前仅在 D76N 突变体中检测到。这种中间状态的形成可能对我们理解 2m 原纤维形成具有重要意义。
