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Originally published as Biophys J. BioFAST on September 17, 2004.
doi:10.1529/biophysj.104.043448
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Biophysical Journal 87:3623-3632 (2004)
© 2004 The Biophysical Society

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

Emma Langella *, Roberto Improta * {dagger} and Vincenzo Barone *

* Dipartimento di Chimica, Università Federico II, Complesso Monte S. Angelo, via Cintia, Naples, Italy; and {dagger} Istituto di Biostrutture e Bioimmagini-CNR Via Mezzocannone 6, I-80134 Naples, Italy

Correspondence: Address reprint requests to Vincenzo Barone, Tel.: 39-081-674206; E-mail: baronev{at}unina.it.

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 ß-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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