Role of the helix capping in the stability of the mouse prion (180-213) segment: investigation through molecular dynamics simulations.

Molecular dynamics simulation of the 180-213 segment, forming the B and C helices in the mouse prion protein, and of three mutants, where the capping box residues or the hydrophobic staple motif residues were selectively mutated, have been carried out. The results indicate that the wild type segment is stable over all the trajectory, whilst the mutants display different degrees of destabilization. In detail mutation of Asp202 brings to a rapid unfolding of helix C likely because of the concomitant loss of a hydrogen bond and of a negative charge able to stabilize the dipole in the first turn of the helix. A lower destabilizing effect is observed upon mutation Thr199. On the other hand mutation of Phe198 and Val203, the hydrophobic staple residues, brings to an incorrect orientation of the first helix relative to the second one due to a weakening of the hydrophobic interaction. The results confirm the importance of the presence of both motifs for the structural integrity of the isolated fragment and suggest that these residues may have a main role in the structural transition observed in the inherited human prion diseases.