The human prion protein a2 helix: a thermodynamic study of its conformational preferences.

We have synthesized both free and terminally-blocked peptide corresponding to the second helical region of the globular domain of normal human prion protein, which has recently gained the attention of structural biologists because of a possible role in the nucleation process and fibrillation of prion protein. The profile of the CD spectrum of the free peptide was that typical of a-helix, but was converted to that of b-structure in about 16 h. Below 2.1 x 10-5 M, the spectrum of the blocked peptide exhibited a single band centered at 200 nm that is unequivocally assocd. with random conformations and did not change even after 24 h. The conformational preferences of the blocked peptide have been investigated as a function of temp., using trifluoroethanol or low-concn. sodium dodecyl sulfate as a- or b-structure inducers, resp. Extrapolation of free energy data to zero concn. of structuring agent showed that the peptide prefers a-helical over b-type organization, in spite of results from prediction algorithms. However, the free energy difference between the two forms, as obtained by a thermodn. cycle, is subtle (roughly 5-8 kJ mol-1 at any temp. from 280 K to 350 K), suggesting conformational ambivalence. This result supports the view that in the prion protein, the structural behavior of the peptide is governed by the cellular microenvironment.