Theoretical Study On Normal Function And Conformational Conversion Of Prion Proteins

The normal function of the prion protein was firstly studied by the quantum chemistry method to shed light on the Cu(II)-binding modes for PrPc and the normal function of prion protein through the comparison of the antioxidant ability with the Cu,Zn-SOD and its mimics. By the combined methods theoretical calculation and bioinformatics the location of the prion protein was also determined. Comparative molecular dynamics simulation studies on the Chicken and Human prion protein have also been performed to explore the mechanisms for PrPc - PrPSC conversion.Prion diseases are disorders with sporadical, infectious and inheritable properties. The conversion of normal prion protein (PrPc) into scrapie isoform (PrPSC) is a key event in the pathogenesis of prion diseases. Despite much effort has been devoted to investigating the conversion of PrPC- PrPSC and the normal function of PrPc, some fundamental questions still remain open. For instance, does the pathogenesis of prion diseases arisefrom the toxicity of PrPSC or the loss of normal function of PrPc ? How is PrPc converted into PrPSC?The density functional theory (DFT) with GAUSSIAN 98 package of programs was employed to explore the normal function of the prion protein and the molecular dynamics simulation method with Insight II package of programs in UNIX system was used to illustrate the mechanisms for PrPc - PrPSC conversion.The most important results are as follows:i. Density functional theory (DFT) method B3LYP/LANL2DZ was employed to calculate the binding energies and electron affinities for various Cu(II)-binding modes of mammalian normal prion protein (PrPc). The calculation results not only provide solid evidence to support one of experimentally determined Cu(II)-binding modes for PrPc, but also shed new light on the normal function of the elusive protein, that is, PrPc is rather a Cu(II) buffer than a Cu(II) transporter or an antioxidant. In addition, the present theoretical methodology is also useful to investigate the metal-chelating properties for other proteins and to rationally design Cu,Zn-SOD mimics.ii. The conversion of normal prion protein (PrPc) into scrapie isoform (PrPSC) is a key event in the pathogenesis of prion diseases. However, the precise conversion mechanism has given rise to much controversy. In this paper, molecular dynamics (MD) simulations have been employed to explore the stability difference of Human PrPc (HuPrPc) andchicken PrPc (CkPrPc) and to investigate the unfolding mechanisms of PrPc-PrPsc conversion. The simulation results indicate that HuPrPc is more stable than CkPrPc, which is opposite to the theoretical prediction. As non-mammals are devoid of prion diseases, the finding implies that other factors than prion protein itself, such as RNA and unknown protein (protein X), may be involved in the pathogenesis of prion diseases. The simulation also reveals that the helix 1 of HuPrPc is less stable than that of CkPrPc, due to the charge repulsion of the crowded negative-charged amino acids in the helix and the flawed electrostatic interaction between Aspl47 and Arg208 in the protein, which provides a possible mechanism for the PrPc-PrPsc conversion. Accordingly, the existing contradictory observations on the conversion can be unified and a possible strategy for preventing prion diseases is proposed, i.e., substituting Asp 147 with a nonpolar amino acid.iii. Through theoretical calculation of the proteins involved in the transportation of the copper ion from the outside to inside of cell, it was found that there exists thennodynamic gradient in the binding energies to facilitate the transportation of the proteins. It has also been proved that prion protein was localized around the cell membrane and this is also in agreement with the experimental result, In addition, the binding energy of the proteins with copper is not determined by the chelating mode, while by the protein in itself.