Checking the pH-Induced Conformational Transition of Prion Protein by Molecular Dynamics Simulations: Effect of Protonation of Histidine Residues

Abstract

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 on the effect of protonation of histidine residues on the conformational behavior of human PrPC globular domain. Our simulations reveal a significant loss of alpha-helix content under mildly acidic conditions, due to destructuration of the C-terminal part of HB (thus suggesting a possible involvement of HB into the conformational transition leading to the pathogenic isoform) and a transient lengthening of the native beta-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 syndrome. Finally, the relevance of our results for the location of a Cu2+-binding pocket in the C-terminal part of the prion is discussed.

Instability of familial spongiform encephalopathy-related prion mutants

“…A recent study indicated that the breaking of the salt bridge (E195-R156) induced by the protonation of H187 at acidic pH was the key event underlying the extension of the S2 region [11]. However, in the present study, there were no differences in either the line shapes or the value of 1/H 0 from the ESR spectra of WT* and H186S at pH 7.5 (Fig.…”

“…3B). These results indicated that the H176 was strongly associated with the stability of S2 regions, although this histidine residue (human 177) was reported to have little effect on the overall spatial arrangement of PrP in an MD simulation study [11].…”

“…In addition, His 187 (H187) has also been reported to be involved into a pathogenic mutation associated with GSS syndrome (H187R), which implies a positively charged residue in position 187, analogous to H187 protonation [9,10]. A recent study suggested that the breaking of the salt bridge between Glu 195 and Arg 156 induced by the protonation of H187 at acidic pH was the key event underlying the extension of the S2 4 region [11]. However, there is no experimental evidence that these amino acids are involved in the structure of PrP C such as the high flexibility of the S2 region.…”

Molecular Dynamics as an Approach to Study Prion Protein Misfolding and the Effect of Pathogenic Mutations

“…At this mildly acidic pH, solvent-exposed glutamate residues may also become protonated and a further decrease to strongly acidic pH (pH ≤ 3.0) will likely result in protonation of all glutamate and aspartate side chains. In line with these values, several MD studies have used differential protonation of side chains to compare the conformational dynamics of human PrP between neutral and strongly acidic pH [56,57,61], neutral and mildly acidic pH [99,100], and all three pH environments [59,101]. The neutral pH environment was represented by using singly protonated (neutral) histidine side chains and all other ionizable side chains charged, mildly acidic pH by all ionizable side chains charged, and strongly acidic pH by all ionizable side chains protonated.…”

A novel copper(II) coordination at His186 in full-length murine prion protein

“…A recent study using molecular dynamic (MD) simulation indicated that the break of the salt bridge between Arg156 and Glu196 induced by the protonation of His187 in human prion protein (His186 in mouse prion protein) at acidic pH was the key event underlying the extension of the S2 region and the conversion to -sheet-rich PrP [31]. Furthermore, His187…”