Conformational studies on the prion protein 115-122 fragment

The conformational properties of the 115-122 region of the prion protein (PrP) were investigated by means of molecular mechanics and DFT computations. From the results of the Monte Carlo Multiple Minimum conformational searches several representative groups could be distinguished. Analysis of these and other characteristic structures like the α-helix and the geometry of the 115-122 region of dissolved PrP (native) revealed the primary importance of N-H⋯O hydrogen bonding interactions in their stabilization, whereas the N-H⋯N interactions play only a marginal role. According to our PBE/TZVPP//RI-PBE/SVP DFT calculations, the isolated β-sheet and α-helical regular secondary structures and the native geometry are less stable than γ-turn, which proved to be the global minimum geometry of the isolated 115-122 PrP fragment. The different solvation energies in aqueous solution, however, change the above picture. The β-sheet structure can be considerable stabilized in water, becoming the most favoured at the PBE/TZVPP//RI-PBE/SVP level using the COSMO solvation model. These results support a possible formation of the β-sheet structure of small PrP fragments involving the 115-122 region in aqueous solution, and in this way the proposed mechanism of their inhibition of the PrP(endogenous) → PrP(pathogenic) conversion.