New Concept on the Phase Space of the Protein : Experiments and Theory

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We found and structurally characterized the folding intermediate of hamster prion protein using high-pressure NMR method (K.Kuwata, Biochemistry, 2002) and designated it as PrP^*. We found that in PrP^*, B-and C-helices are preferentially disordered, while A-helix remains intact. Especially residues locate at the interface with the beta sheet (S2) are extremely unstable. It is highly possible that partially unfolded PrP^* is involved in the structural conversion reaction from PrP^C to PrP^<Sc>.We also clarified the three dimensional structure of oligomeric duster of PrP106-126, a peptide corresponding to the hydrophobic cluster of prion protein, using electron microscopy, circular dichroism, NMR and molecular dynamics simulation (K Kuwata Proc.Natl.Acad.Sci, 2003). The oligomeric conformation of PrP106-126 dusterwas stabilized by the hydrophobic interaction between methyl moieties.In hamster prion, residues exchanging on a time scale of micro-to milliseconds using CPMG relaxation dispersion method some what correspond to those exhibit low stability in high-pressure NMR method (Kuwata et al., Biochemistry, 2004). Moreover the distribution of those unstable residues is correlated with those involved in the causative mutation. Thus these residues may be responsible for the conformational conversion from PrPC to PrP^<Sc>.Furthermore we formulated a novel mathematical representation of the protein dynamics using the number theoretical description.