Molecular dynamics simulations capture the misfolding of the bovine prion protein at acidic pH.
Molecular dynamics simulations capture the misfolding of the bovine prion protein at acidic pH.
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DOI：
10.3390/biom4010181
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发表时间：
2014-02-10
期刊：
影响因子：
5.5
通讯作者：
Daggett V
中科院分区：
文献类型：
--
作者：
Cheng CJ;Daggett V
牛海绵状脑病(BSE)，或疯牛病，是一种致命的神经退行性疾病，可传播给人类，目前是无法治愈的。疯牛病是由PrP引起的，PrP采用两种构象；PrPC是天然的无害形式，富含α-螺旋；PrPSc是富含β-折叠的错折叠形式，具有传染性并形成神经毒性物种。酸性pH诱导PrPc向PrPSc转化。我们对不同pH条件下的牛PrP进行了分子动力学模拟。酸性的pH环境引起了在中性pH模拟中没有观察到的构象变化。在酸性pH模拟中，发现了推测的错误折叠结构，在柔性的N-末端结构域中形成了非本地的β-链。观察到两条不同的形成非本地β链的途径：在低pH时，与M129的疏水接触使非本地β链成核；在中等pH时，涉及Q168和D178的极性接触促进了柔性N-末端发夹的形成。这些中低pH模拟捕捉了非本地β链的形成过程，从而提高了我们对PrPC如何错误折叠到富含β-Sheet的PrPSc以及pH因素如何影响这一过程的理解。
Bovine spongiform encephalopathy (BSE), or mad cow disease, is a fatal neurodegenerative disease that is transmissible to humans and that is currently incurable. BSE is caused by the prion protein (PrP), which adopts two conformers; PrPC is the native innocuous form, which is α-helix rich; and PrPSc is the β-sheet rich misfolded form, which is infectious and forms neurotoxic species. Acidic pH induces the conversion of PrPC to PrPSc. We have performed molecular dynamics simulations of bovine PrP at various pH regimes. An acidic pH environment induced conformational changes that were not observed in neutral pH simulations. Putative misfolded structures, with nonnative β-strands formed in the flexible N-terminal domain, were found in acidic pH simulations. Two distinct pathways were observed for the formation of nonnative β-strands: at low pH, hydrophobic contacts with M129 nucleated the nonnative β-strand; at mid-pH, polar contacts involving Q168 and D178 facilitated the formation of a hairpin at the flexible N-terminus. These mid- and low pH simulations capture the process of nonnative β-strand formation, thereby improving our understanding of how PrPC misfolds into the β-sheet rich PrPSc and how pH factors into the process.