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. 2004 Dec;87(6):3623-32.
doi: 10.1529/biophysj.104.043448. Epub 2004 Sep 17.

Checking the pH-induced conformational transition of prion protein by molecular dynamics simulations: effect of protonation of histidine residues

Emma Langella  1 , Roberto Improta, Vincenzo Barone
Affiliations

Checking the pH-induced conformational transition of prion protein by molecular dynamics simulations: effect of protonation of histidine residues

Emma Langella et al. Biophys J. 2004 Dec.

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.

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Figures

FIGURE 1
FIGURE 1
Final structures of PrPN (left) and PrPH (right) runs. Labels used to indicate secondary structure elements and connecting regions are also shown. Histidine residues (140, 155, 177, 187) are displayed in sticks.
FIGURE 2
FIGURE 2
Root mean-square deviation of the Cα carbon atoms positions from their positions in the starting NMR structure as a function of time in the PrPN (dashed line) and PrPH (solid line) runs.
FIGURE 3
FIGURE 3
Secondary structure of PrPN (upper panel) and PrPH (lower panel) as a function of time, determined with DSSP.
FIGURE 4
FIGURE 4
Side chains minimum distance between His155 and Glu-196 (black) and between His-187 and Glu-196 (shaded line) as a function of time in PrPH trajectory. Distance between Ser-132 carboxylic and Val-161 amidic groups is also shown (light shaded line).
FIGURE 5
FIGURE 5
Secondary structure of test1 (upper panel) and test2 (lower panel) as a function of time, determined with DSSP.
FIGURE 6
FIGURE 6
Side chains minimum distance between His-155 and Glu-196 (black line) and between His-187 and Glu-196 (gray line) as a function of time in test1 (upper panel) and test2 (lower panel) runs.
FIGURE 7
FIGURE 7
PrPH structure at 5.5 ns. Lengthening of native β-sheet can be observed. Residues His-155, His-187, and Glu-196 are displayed in stick.
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