The Role of Electrostatic Interaction in Triggering the Unraveling of Stable Helix 1 in Normal Prion Protein.A Molecular Dynamics Simulation Investigation
The conversion of normal prion protein (PrpC) into scrapie isoform (PrPSc) is a key event in the pathogenesis of prion diseases. However, the conversion mechanism has given rise to much controversy. For instance, there is much debate on the behavior of helix 1 (HI) in the conversion. A series of experiments demonstrated that H1 in isolated state was very stable under a variety of conditions. But, other experiments indicated that helices 2 and 3 rather than H1 were retained in PrPSc. In this paper, molecular dynamics (MD) simulation is employed to investigate the dynamic behavior of HI. It is revealed that although the helix 1 of Human PrPC (HuPrPC) is very stable in the isolated state, it becomes unstable when incorporated into native HuPrPC, which likely results from the long-range electrostatic interaction between Aspl47 and Arg208 located in the helices 1 and 3, respectively. This expla nation is supported by experimental evaluation and MD simulation on D147N mutant of HuPrpC that the mutant becomes a little more stable than the wild type HuPrpC. This find ing not only help to reconcile the existing debate on the role of helix 1 in the PrPC→PrPSc transition, but also reveals a possible mechanism for triggering the PrPc→PrPSc conversion.
Hong-Fang Ji Hong-Yu Zhang Liang Shen
Laboratory for Computational Biology and Shandong Provincial Research Center for Bioinformatic Engineering and Technique Shandong University of Technology Zibo 255049, P. R.China
国际会议
杭州
英文
1469-1476
2007-04-01（万方平台首次上网日期，不代表论文的发表时间）