Fragment molecular orbital calculations reveal that the E200K mutation markedly alters local structural stability in the human prion protein.
The E200K mutation of the human prion protein (PrP) is known to cause familial Creutzfeldt-Jakob disease. In order to elucidate the effects of the mutation on the local structural stability of PrP, we performed ab initio fragment molecular orbital calculations for the wild-type human PrP and the E200K variant modeled under neutral and mild acidic conditions. The calculations revealed that this substitution markedly altered the intramolecular interactions in the PrP, suggesting that the local structural instabilities induced by the E200K mutation might cause initial denaturation of the PrP and its subsequent conversion to a pathogenic form. This work presents a new approach for quantitatively elucidating structural instabilities in proteins that cause misfolding diseases.
Hasegawa
Koji
K
AdvanceSoft Corporation, Akasaka, Tokyo, Japan. khasegawa@advancesoft.jp
Mohri
Shirou
S
Yokoyama
Takashi
T
D000595:Amino Acid Sequence; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D011328:Prions / Q000737:chemistry* / Q000235:genetics*; D055550:Protein Stability; D017433:Protein Structure, Secondary
D011328:Prions