Computational Analysis for Amyloid Formation

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The developing mechanism of prion diseases has remained unclear. In this study, based on molecular dynamics simulations, we investigated the structural instability in prion protein (PrP), which promotes a partial helix-to-sheet conformational conversion. This instability of PrP facilitates the formation of active intermediate precursors (PrP*) that can lead to the conformational conversion of the normal prion protein (PrPC) to the pathogenic isoform (PrPSc). We propose a novel method to systematically construct a free-energy landscape by mapping massive protein structural data into a reduced space according to their secondary structures, named secondary structure principal component analysis (SSPCA). The definite existence of PrP* was confirmed in the free-energy landscape. The existence ratio in number of PrP* to its normal form was estimated to be 0.07. The SSPCA method has great potential to solve various challenges in studying highly flexible molecular systems, other than PrPs.