The Role of Electrostatic Interaction in Triggering the Unraveling of Stable Helix 1 in Normal Prion Protein. A Molecular Dynamics Simulation Investigation

摘要

The conversion of normal prion protein (PrP~C) into scrapie isoform (PrP~(Sc)) 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 PrP~(Sc). 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 PrP~C (HuPrP~C) is very stable in the isolated state, it becomes unstable when incorporated into native HuPrP~C, 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 HuPrP~C that the mutant becomes a little more stable than the wild type HuPrP~C. This finding not only help to reconcile the existing debate on the role of helix 1 in the Prp~C → PrP~(Sc) transition, but also reveals a possible mechanism for triggering the PrP~C → PrP~(Sc) conversion.