Theoretical study of the prion protein based on the fragment molecular orbital method

Abstract

We performed fragment molecular orbital (FMO) calculations to examine the molecular interactions between the prion protein (PrP) and GN8, which is a potential curative agent for prion diseases. This study has the following novel aspects: we introduced the counterpoise method into the FMO scheme to eliminate the basis set superposition error and examined the influence of geometrical fluctuation on the interaction energies, thereby enabling rigorous analysis of the molecular interaction between PrP and GN8. This analysis could provide information on key amino acid residues of PrP as well as key units of GN8 involved in the molecular interaction between the two molecules. The present FMO calculations were performed using an original program developed in our laboratory, called "Parallelized ab initio calculation system based on FMO (PAICS)".

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

“…15,22 Our calculations showed that the L2-α2 region with weak interactions in the neutral pH was considerably destabilized under mild acidic pH condition, although the structural stability of the L2-L4 region with strong attractive interaction in the neutral pH model did not alter considerably in the mild acidic pH ( Table 3 and Fig. 2).…”

“…Although the FMO calculations at the MP2 level can provide quantitative information on the molecular interactions between the residues in a protein, [12][13][14][15] such an analysis based on individual interactions involves enormous computational complexity; for example, PrP129-224, which contains ∼100 residues, could have more than 5,000 molecular interaction energies for residue pairs. Conversion of the intramolecular interactions between residues into those for secondary structure elements or pairs dramatically reduces the computational complexity and eases the interpretation of the calculation results.…”

“…This result may suggest that the binding of GN8, especially to L2-α2 region in the endosomes, was effective in structurally stabilizing PrP, partially supporting the proposed mechanism of GN8. 15,22 The structural stability of the entire PrP can be observed by protein denaturation measurements. 23 The observed thermodynamic stability of the wild-type human PrP is similar to that of the E200K variant; 23 this is consistent with the calculation results of the total ∆E Pair values ( Table 3).…”

“…10,11 This method has been used to quantify the inter-and intramolecular interactions in various proteins and nucleic acids-interactions that contribute to the binding affinities and structural stabilities of these molecules. [12][13][14][15] Very recently, this method has been successfully used to reveal the intermolecular interactions between PrP and an anti-prion drug. 15 In this study, we performed the FMO calculations on the globular domain of wild-type human PrP and the E200K variant in order to elucidate the differences in their intramolecular interactions and thus their local structural stabilities.…”

“…[12][13][14][15] Very recently, this method has been successfully used to reveal the intermolecular interactions between PrP and an anti-prion drug. 15 In this study, we performed the FMO calculations on the globular domain of wild-type human PrP and the E200K variant in order to elucidate the differences in their intramolecular interactions and thus their local structural stabilities. This is the first study on the application of FMO calculations for investigating the intramolecular interactions in the PrP; the method represents a new approach for the structural analysis of proteins.…”