The structural transformation comparison of the human Prion protein mutants V176G, E196A, and I215V by using molecular dynamics simulation
Abstract The point mutations in the gene coding of prion protein (PrP) originate human familial prion protein (HuPrP) diseases. Such diseases are caused by several amino acid mutations of HuPrP including V176G, I215V, and E196A located at the second, third native helix and in their loop, respectively. Determining the transition from cellular prion protein (PrPc) to pathogenic conformer (PrPSc) in the globular domain of HuPrP that results in pathogenic mutations is the key issue. The effects of mutation on monomeric PrP are detected in the absence of an unstructured N-terminal domain only. A MD simulation for each of these wild type mutants is performed to examine their structure in the aqueous media. The structural determinants are discerned to be different for wild-type HuPrP (125–228) variants compare to that of HuPrP mutations. These three mutations exhibiting diverse effects on the dynamical properties of PrP are attributed to the variations in the secondary structure, solvent accessible surface areas (SASAs), and salt bridges in the globular domain of HuPrP. High fluctuations that are evidenced around residues of the C-terminus of the helix 1 for V176G cause Gerstmann-Straussler-Scheinker (GSS) syndrome. Conversely, the occurrence of fluctuations around residues of helix 2, helix 3, and the loss of salt bridges in these regions for E196A and I215V mutants is responsible for Creutzfeldt-Jakob disease. Furthermore, small changes in the overall SASAs mutations strongly influence the intermolecular interactions during the aggregation process. The comparative results in this study demonstrate that the three mutants undergo different pathogenic transformations.