Journal
PRION
Volume 4, Issue 1, Pages 38-44Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/pri.4.1.10890
Keywords
prion; Creutzfeldt-Jakob disease; fragment molecular orbital calculation; molecular interaction; structural stability
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Funding
- Ministry of Agriculture, Forestry and Fisheries Research Network (MAFFIN)
- BSE
- Ministry of Agriculture, Forestry and Fisheries, Japan
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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.
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