Molecular dynamics simulation studies of novel Q212H, V203G, and N173K mutations in prion diseases

Abstract

Prion diseases in humans are grouped based on whether they are sporadic, inherited, or acquired. In inherited prion disease, abnormal prion proteins (PrP) are produced through a genetic mutation of which 40 point mutations have been discovered. Three novel mutations V203G, Q212H and N173K have been reported, but remained questionable whether the mutations caused the prion disease. In this research, we preformed molecular dynamics simulations and structural analysis to investigate if these novel CJD related mutations behave similarly to known disease causing mutations in the same region of the protein. The results show similar dynamic behavior to pathogenic mutations V203I and Q212P, but differ when compared to the non-pathogenic N171S polymorphism. All three mutations V203G, Q212H and N173K showed a decrease in the protein's overall stability, an slight increase in flexibility, a major loss in salt bridges in the first and second helix, changes in the electrostatic surface of PrP and an increase in the solvent exposure of the protein, all of which are common dynamic behaviors of among pathogenic prion mutations.