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.