NR ASJX
AU Ji,H.F.; Zhang,H.Y.; Shen,L.
TI The role of electrostatic interaction in triggering the unraveling of stable helix 1 in normal prion protein. A molecular dynamics simulation investigation.
QU Journal of Biomolecular Structure and Dynamics 2005 Apr; 22(5): 563-70
PT journal article
AB 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 (H1) 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 H1. 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 Asp147 and Arg208 located in the helices 1 and 3, respectively. This explanation 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 finding 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.
MH Aspartic Acid/genetics/metabolism; Computer Simulation; Electrostatics; Humans; Models, Molecular; Mutation; Prions/*chemistry/genetics/*metabolism; Protein Denaturation; Protein Structure, Secondary; Research Support, Non-U.S. Gov't
AD Laboratory for Computational Biology, Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Shandong University of Technology, Zibo 255049, PR China.
SP englisch
PO USA