Unraveling the molecular mechanism of prion disease: Insights from α2 area mutations in human prion protein

Abstract

Prion diseases are a class of fatal neurodegenerative diseases caused by misfolded prion proteins. The main reason is that pathogenic prion protein has a strong tendency to aggregate, which easily induces the damage to the central nervous system. Point mutations in the human prion protein gene can cause prion diseases such as Creutzfeldt–Jakob and Gerstmann’s syndrome. To understand the mechanism of mutation-induced prion protein aggregation, the mutants in an aqueous solution are studied by molecular dynamics simulations, including the wild type, V180I, H187R and a double point mutation which is associated with CJD and GSS. After running simulations for 500 ns, the results show that these three mutations have different effects on the kinetic properties of PrP. The high fluctuations around the N-terminal residues of helix 2 in the V180I variant lead to a decrease in hydrogen bonding on helix 2, while an increase in the number of hydrogen bonds between the folded regions promotes the generation of β-sheet. Meanwhile, partial deletion of salt bridges in the H187R and double mutants allows the sub-structural domains of the prion protein to separate, which would accelerate the conversion from PrPC to PrPSc. A similar trend is observed in both SASA and Rg for all three mutations, indicating that the conformational space is reduced and the structure is compact.