The first step in the formation of the protease resistant form (PrP Sc ) of prion proteins involves a conformational transition of the monomeric cellular form of PrP C to a more stable aggregation prone state PrP C* . A search of PDBselect and Escherichia coli and yeast genomes shows that the exact pattern of charges in helix 1 (H1) is rare. Among the 23 fragments in PDBselect with the pattern of charges that match H1, 83% are helical. Mapping of the rarely found (in E. coli and yeast genomes) hydrophobicity patterns in helix 2 (H2) to known secondary structures suggests that the PrP C → PrP C* transition must be accompanied by alterations in conformations in second half of H2. We probe the dynamical instability in H1 and in the combined fragments of H2 and helix 3 (H3) from mPrP C (H2+H3), with intact disulfide bond, using all atom molecular dynamics (MD) simulations totaling 680 ns. In accord with recent experiments, we found that H1 is helical, whereas the double mutant H1[D147A–R151A] is less stable, implying that H1 is stabilized by the ( i , i + 4) charged residues. The stability of H1 suggests that it is unlikely to be involved in the PrP C → PrP C* transition. MD simulations of H2+H3 shows that the second half of H2 (residues 184–194) and parts of H3 (residues 200–204 and 215–223) undergo a transition from α-helical conformation to a β and/or random coil state. Simulations using two force fields (optimized potentials for liquid simulations and charmm ) give qualitatively similar results. We use the MD results to propose tentative structures for the PrP C* state.