State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
J Struct Biol. 2012 Jun;178(3):225-32. doi: 10.1016/j.jsb.2012.03.009. Epub 2012 Apr 3.
The central event in the pathogenesis of prion protein (PrP) is a profound conformational change from its α-helical (PrP(C)) to its β-sheet-rich isoform (PrP(Sc)). Many single amino acid mutations of PrP are associated with familial prion diseases, such as D202N, E211Q, and Q217R mutations located at the third native α-helix of human PrP. In order to explore the underlying structural and dynamic effects of these mutations, we performed all-atom molecular dynamics (MD) simulations for the wild-type (WT) PrP and its mutants. The obtained results indicate that these amino acid substitutions have subtle effects on the protein structures, but show large changes of the overall electrostatic potential distributions. We can infer that the changes of PrP electrostatic surface due to the studied mutations may influence the intermolecular interactions during the aggregation process. In addition, the mutations also affect the thermodynamic stabilities of PrP.
朊病毒蛋白（PrP）发病机制的核心事件是其从α-螺旋（PrP(C))到富含β-折叠的异构体（PrP(Sc))的深刻构象变化。许多 PrP 的单一氨基酸突变与家族性朊病毒病有关，例如位于人 PrP 第 3 个天然α-螺旋的 D202N、E211Q 和 Q217R 突变。为了探索这些突变的潜在结构和动力学影响，我们对野生型（WT）PrP 及其突变体进行了全原子分子动力学（MD）模拟。得到的结果表明，这些氨基酸取代对蛋白质结构只有细微影响，但对整体静电势分布有较大变化。我们可以推断，研究中突变引起的 PrP 静电表面的变化可能会影响聚集过程中的分子间相互作用。此外，突变还会影响 PrP 的热力学稳定性。
