Disassociation of β1-α1-β2 from the α2-α3 domain of prion protein (PrP) is a prerequisite for the conformational conversion of PrP into PrP: Driven by the free energy landscape.

Misfolding of the cellular prion protein (PrP) into β-sheet-rich scrapie form (PrP) is associated with transmissible spongiform encephalopathies. A point mutation F198S is responsible for the development of a rare inherited Gerstmann-Straussler-Scheinker disease caused by the aggregation of PrP. Thus, identification and the structural characterization of aggregation-prone regions are essential to delineate the conversion of PrP to the disease-associated PrP upon F198S mutation. In the present study, molecular dynamics simulations on the wild-type PrP (WT-PrP) and its mutant were performed to explore the structural basis responsible for aggregation driven by the mutation. Secondary structure analysis revealed that the mutant exhibited a partial unfolding on α2 and the complete distortion in the 3-helix of the β2-α2 loop. Remarkably, the β2-α2 loop is in proximity to α3 attributed by the long-range hydrophobic interactions and such structural intimacy is not observed in the WT-PrP. Owing to this, the β1-α1-β2 regions have separated from α2-α3 domain resulting in the impairment on the hydrogen bond between α1 and α3. Thus, the present study provides a detailed structural description of the F198S mutant in line with previous experimental results and delivers insights into the structural basis responsible for the conversion of PrP to the disease-associated PrP.