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The first step in the formation of the protease resistant form (PrPSc) of prion proteins involves a conformational transition of the monomeric cellular form of PrPC to a more stable aggregation prone state PrPC*. 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 PrPC--&gt;PrPC* 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 mPrPC (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 PrPC--&gt;PrPC* 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 alpha-helical conformation to a beta 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 PrPC* state.

Probing the instabilities in the dynamics of helical fragments from mouse PrP C

Probing the instabilities in the dynamics of helical fragments from mouse PrP ^C