Identification of two early folding stage prion non‐local contacts suggested to serve as key steps in directing the final fold to be either native or pathogenic

The initial steps of the folding pathway of the C‐terminal domain of the murine prion protein mPrP(90–231) are predicted based on the sequential collapse model (SCM). A non‐local dominant contact is found to form between the connecting region between helix 1 and β‐sheet 1 and the C‐terminal region of helix 3. This non‐local contact nucleates the most populated molten globule‐like intermediate along the folding pathway. A less stable early non‐local contact between segments 120–124 and 179–183, located in the middle of helix 2, promotes the formation of a less populated molten globule‐like intermediate. The formation of the dominant non‐local contact constitutes an example of the postulated Nature’s Shortcut to the prion protein collapse into the native structure. The possible role of the less populated molten globule‐like intermediate is explored as the potential initiation point for the folding for three pathogenic mutants (T182A, I214V, and Q211P in mouse prion numbering) of the prion protein.