Chamachi Neharika G, Chakrabarty Suman
Physical and Materials Chemistry Division, CSIR-National Chemical Laboratory , Pune 411008, India.
J Phys Chem B. 2016 Aug 4;120(30):7332-45. doi: 10.1021/acs.jpcb.6b03690. Epub 2016 Jul 22.
The pathological forms of prions are known to be a result of misfolding, oligomerization, and aggregation of the cellular prion. While the mechanism of misfolding and aggregation in prions has been widely studied using both experimental and computational tools, the structural and energetic characterization of the dimer form have not garnered as much attention. On one hand dimerization can be the first step toward a nucleation-like pathway to aggregation, whereas on the other hand it may also increase the conformational stability preventing self-aggregation. In this work, we have used extensive all-atom replica exchange molecular dynamics simulations of both monomer and dimer forms of a mouse prion protein to understand the structural, dynamic, and thermodynamic stability of dimeric prion as compared to the monomeric form. We show that prion proteins can dimerize spontaneously being stabilized by hydrophobic interactions as well as intermolecular hydrogen bonding and salt bridge formation. We have computed the conformational free energy landscapes for both monomer and dimer forms to compare the thermodynamic stability and misfolding pathways. We observe large conformational heterogeneity among the various modes of interactions between the monomers and the strong intermolecular interactions may lead to as high as 20% β-content. The hydrophobic regions in helix-2, surrounding coil regions, terminal regions along with the natively present β-sheet region appear to actively participate in prion-prion intermolecular interactions. Dimerization seems to considerably suppress the inherent dynamic instability observed in monomeric prions, particularly because the regions of structural frustration constitute the dimer interface. Further, we demonstrate an interesting reversible coupling between the Q160-G131 interaction (which leads to inhibition of β-sheet extension) and the G131-V161 H-bond formation.
已知朊病毒的病理形式是细胞朊病毒错误折叠、寡聚化和聚集的结果。虽然使用实验和计算工具对朊病毒的错误折叠和聚集机制进行了广泛研究，但二聚体形式的结构和能量表征并未得到同样多的关注。一方面，二聚化可能是通向类似成核聚集途径的第一步，而另一方面，它也可能增加构象稳定性以防止自我聚集。在这项工作中，我们对小鼠朊病毒蛋白的单体和二聚体形式进行了广泛的全原子副本交换分子动力学模拟，以了解与单体形式相比二聚体朊病毒的结构、动力学和热力学稳定性。我们表明，朊病毒蛋白可以通过疏水相互作用以及分子间氢键和盐桥的形成自发二聚化并得到稳定。我们计算了单体和二聚体形式的构象自由能景观，以比较热力学稳定性和错误折叠途径。我们观察到单体之间各种相互作用模式存在很大的构象异质性，并且强烈的分子间相互作用可能导致高达20%的β含量。螺旋2中的疏水区域、周围的卷曲区域、末端区域以及天然存在的β折叠区域似乎积极参与朊病毒-朊病毒分子间相互作用。二聚化似乎大大抑制了单体朊病毒中观察到的固有动态不稳定性，特别是因为结构受挫区域构成了二聚体界面。此外，我们证明了Q160-G131相互作用（导致β折叠延伸的抑制）和G131-V161氢键形成之间存在有趣的可逆耦合。
