The D76N mutant of the protein is a biologically motivated model system to study protein aggregation. There is strong experimental evidence, supported by molecular simulations, that D76N populates a highly dynamic conformation (which we originally named ) that exposes aggregation-prone patches as a result of the detachment of the two terminal regions. Here, we use Molecular Dynamics simulations to study the stability of an ensemble of dimers of generated via protein–protein docking. MM-PBSA calculations indicate that within the ensemble of investigated dimers the major contribution to interface stabilization at physiological pH comes from hydrophobic interactions between apolar residues. Our structural analysis also reveals that the interfacial region associated with the most stable binding modes are particularly rich in residues pertaining to both the N- and C-terminus, as well residues from the BC- and DE-loops. On the other hand, the less stable interfaces are stabilized by intermolecular interactions involving residues from the CD- and EF-loops. By focusing on the most stable binding modes, we used a simple geometric rule to propagate the corresponding dimer interfaces. We found that, in the absence of any kind of structural rearrangement occurring at an early stage of the oligomerization pathway, some interfaces drive a self-limited growth process, while others can be propagated indefinitely allowing the formation of long, polymerized chains. In particular, the interfacial region of the most stable binding mode reported here falls in the class of self-limited growth.

中文翻译：

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[公式省略]2-微球蛋白 D76N 突变体的模拟二聚体预测稳定结合模式


该蛋白质的 D76N 突变体是研究蛋白质聚集的生物学驱动模型系统。有强有力的实验证据（得到分子模拟的支持）表明，D76N 形成一种高度动态的构象（我们最初将其命名为 ），由于两个末端区域的分离，该构象暴露出易于聚集的斑块。在这里，我们使用分子动力学模拟来研究通过蛋白质-蛋白质对接生成的二聚体整体的稳定性。 MM-PBSA 计算表明，在所研究的二聚体整体中，生理 pH 下界面稳定的主要贡献来自非极性残基之间的疏水相互作用。我们的结构分析还表明，与最稳定的结合模式相关的界面区域特别富含与 N 端和 C 端相关的残基，以及来自 BC 环和 DE 环的残基。另一方面，不太稳定的界面通过涉及 CD 环和 EF 环残基的分子间相互作用来稳定。通过关注最稳定的结合模式，我们使用简单的几何规则来传播相应的二聚体界面。我们发现，在低聚途径的早期阶段没有发生任何结构重排的情况下，一些界面驱动自限性生长过程，而另一些界面则可以无限传播，从而形成长聚合链。特别是，这里报道的最稳定结合模式的界面区域属于自限生长类别。