Fragment molecular orbital calculations reveal that the E200K mutation markedly alters local structural stability in the human prion protein

Abstract

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.

Acknowledgements

We are very grateful to Dr. T. Nakano, National Institute of Health Science, for his kind support. We also thank Drs. O. Hino and M. Kobayashi, AdvanceSoft Corporation, for their helpful advice. The numerical calculations were supported by the Ministry of Agriculture, Forestry and Fisheries Research Network (MAFFIN). This study was supported by a Grant-in-Aid from the BSE and other Prion Disease Control Projects of the Ministry of Agriculture, Forestry and Fisheries, Japan.

Figures and Tables

Figure 1

Figure 2

Table 1 Selected interfragment interaction energies (IFIEs) between Glu200 in the wild-type PrP or Lys200 in the E200K variant and each amino acid residue, calculation performed at the FMO-MP2/6-31G level

Table 2 The internal interaction energies (ΔE^Int) of the wild-type PrP and E200K variant modeled at neutral pH

Table 3 The pair interaction energies (ΔE^Pair) of the wild-type PrP and E200K variant modeled under neutral and mild acidic conditions