Mutation-Dependent Refolding of Prion Protein Unveils Amyloidogenic-Related Structural Ramifications: Insights from Molecular Dynamics Simulations.

ABSTRACT

The main focus of prion structural biology studies is to understand the molecular basis of prion diseases caused by misfolding, and aggregation of the cellular prion protein PrPC remains elusive. Several genetic mutations are linked with human prion diseases and driven by the conformational conversion of PrPC to the toxic PrPSc. The main goal of this study is to gain a better insight into the molecular effect of disease-associated V210I mutation on this process by molecular dynamics simulations. This inherited mutation elicited copious structural changes in the ß1-α1-ß2 subdomain, including an unfolding of a helix α1 and the elongation of the ß-sheet. These unusual structural changes likely appeared to detach the ß1-α1-ß2 subdomain from the α2-α3 core, an early misfolding event necessary for the conformational conversion of PrPC to PrPSc. Ultimately, the unfolded α1 and its prior ß1-α1 loop further engaged with unrestrained conformational dynamics and were widely considered as amyloidogenic-inducing traits. Furthermore, the resulting folding intermediate possesses a highly unstable ß1-α1-ß2 subdomain, thereby enhancing the aggregation of misfolded PrPC through intermolecular interactions between frequently refolding regions. Briefly, these remarkable changes as seen in the mutant ß1-α1-ß2 subdomain are consistent with previous experimental results and thus provide a molecular basis of PrPC misfolding associated with the conformational conversion of PrPC to PrPSc.