Secondary Structure Principal Component Analysis of Protein: Conformational State of Prion Prone Intermediate

Abstract

We propose a straightforward method to extract the essential information regarding secondary structure interconversions from molecular dynamics simulations of proteins. Based on the method, named secondary structure principal component analysis (SSPCA), we have been studying about intrinsic disorder proteins, structurally ambivalent peptides, and chameleon sequences, which lack a strong intrinsic secondary structure, thus promoting alpha-sheet/beta-strand conformational conversions. We applied the SSPCA method to prion protein (PrP). In the early stage of prion diseases, secondary structure conversion in PrP causing beta-sheet expansion facilitates the formation of a pathogenic isoform with a high content of beta-sheets and strong aggregation tendency to form amyloid fibrils. The definite existence of a PrP isoform with an increased beta-sheet structure was confirmed in a free-energy landscape constructed by mapping protein structural data into a reduced space according to the principal components determined by the SSPCA.