Molecular dynamics simulation of human prion protein

The 1997 Nobel Prize was awarded to Stanley B. Prusiner for his discovery of prions and there are now wet lab experimental results available which show the evidence of such kind of molecules. Present studies reveal the role of acidic pH in the conversion of human prion protein to the pathogenic isoform is investigated by means of molecular dynamics simulations, focusing the attention to the effect of protonation of histidine residues on the conformational behavior of human PrPC globular domain. The simulations reveal a significant loss of α-helix content under mildly acidic conditions, due to destructuration of the C-terminal part of HB, there are three helices present in the protein HA, HB, HC, (thus suggesting a possible involvement of HB into the conformational transition leading to the pathogenic isoform) and a transient lengthening of the native β-sheet. Protonation of His-187 and His-155 seems to be crucial for the onset of the conformational rearrangement. This finding can be related to the existence of a pathogenic mutation, H187R, which is associated with GSS (Gerstmann Straussler Syndrome) syndrome.