Cheng Chin Jung, Koldsø Heidi, Van der Kamp Marc W, Schiøtt Birgit, Daggett Valerie
Department of Bioengineering, University of Washington, Seattle, Washington, USA.
Department of Chemistry, inSPIN and iNANO Centers, Aarhus University, Aarhus C, Denmark.
J Neurochem. 2017 Jul;142(1):171-182. doi: 10.1111/jnc.14044. Epub 2017 May 22.
Prion diseases are associated with the misfolding of the prion protein (PrP) from its normal cellular form (PrP ) to its infectious scrapie form (PrP ). Post-translational modifications in PrP in vivo can play an important role in modulating the process of misfolding. To gain more insight into the effects of post-translational modifications in PrP structure and dynamics and to test the hypothesis that such modifications can interact with the protein, we have performed molecular dynamics simulations of diglycosylated human PrP bound to a lipid bilayer via a glycophosphatidylinositol anchor. Multiple simulations were performed at three different pH ranges to explore pH effects on structure and dynamics. In contrast to simulations of protein-only PrP , no large effects were observed upon lowering the pH of the system. The protein tilted toward the membrane surface in all of the simulations and the putative PrP oligomerization sites became inaccessible, thereby offering a possible protective mechanism against PrP -induced misfolding of PrP .
朊病毒疾病与朊病毒蛋白（PrP）从其正常细胞形式（PrP ）错误折叠为其传染性羊瘙痒病形式（PrP ）有关。体内PrP的翻译后修饰在调节错误折叠过程中可能起重要作用。为了更深入了解翻译后修饰对PrP结构和动力学的影响，并检验这种修饰可与蛋白质相互作用的假设，我们对通过糖基磷脂酰肌醇锚定与脂质双层结合的双糖基化人PrP进行了分子动力学模拟。在三个不同的pH范围内进行了多次模拟，以探索pH对结构和动力学的影响。与仅蛋白质的PrP模拟不同，降低系统pH时未观察到显著影响。在所有模拟中，蛋白质都向膜表面倾斜，假定的PrP寡聚化位点变得无法接近，从而提供了一种可能的保护机制，防止PrP 诱导的PrP错误折叠。
