Determination of solution conformations of PrP106-126, a neurotoxic fragment of prion protein, by H-1 NMR and restrained molecular dynamics

Experimental two-dimensional H-1 NMR data have been obtained for PrP106-128 under the following solvent conditions: deionized water/2,2,2-trifluoroeth anol 50:50 (v/v) and dimethylsulfoxide. These data were analyzed by restrai ned molecular mechanics calculations to determine how changes in solvation affect the conformation of the peptide. In deionized water at pH 3,5, the p eptide adopted a helical conformation in the hydrophobic region spanning re sidues Met112-Leu125, with the most populated helical region corresponding to the Ala115-Ala119 segment (approximate to 10%). In trifluoroethanol/H2O, the alpha-helix increased in population especially in the Gly119-Val122 tr act (approximate to 25%). The conformation of this region was found to be r emarkably sensitive to pH, as the Ala120-Gly124 tract shifted to an extende d conformation at pH 7. In dimethylsulfoxide, the hydrophobic cluster adopt ed a prevalently extended conformation. For all tested solvents the region spanning residues Asn108-Met112 was present in a 'turn-like' conformation a nd included His111, situated just before the starting point of the alpha-he lix. Rather than by conformational changes, the effect of His111 is exerted by changes in its hydrophobicity, triggering aggregation. The amphiphilic properties and the pH-dependent ionizable side-chain of His111 may thus be important for the modulation of the conformational mobility and heterogenei ty of PrP106-126.