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Updated: Jun 8, 2026
Protein Misfolding Cyclic Amplification of Prions
Published on: November 7, 2012
Constant-pH molecular dynamics simulations reveal a β-rich form of the human prion protein
Sara R R Campos1, Miguel Machuqueiro, António M Baptista
1Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Av. da República, EAN, 2780-157 Oeiras, Portugal.
Abstract:
The misfolding of the prion protein (PrP) into a pathogenic β-rich form (PrP(Sc)) has been suggested to occur in the endocytic pathway, triggered by low pH. In this work we performed several constant-pH molecular dynamics simulations of human PrP 90-231 in the pH range 2-7, totaling more than 2 μs. We observed a strong conformational pH dependence where on average the helix content decreased and the β content increased toward acidic pH. Unlike some proposed models, the flexible N-terminus region did not gain stable structure at low pH. Rather, the main structural changes occurred on the helix-rich C-terminus core, as proposed in other models, namely, in the regions around 135-155 and 185-200. The protonation of His187 is found to be associated with a loss of interaction between two PrP subdomains, potentially playing a major role in the misfolding process. In one of the simulations at pH 2, a stable β-rich structure was formed that may be an intermediate of PrP(Sc) formation, indicating that misfolding may precede dimerization.
Insights
Prion protein (PrP) misfolding is pH-dependent, with acidic conditions promoting a pathogenic β-rich structure. Molecular dynamics simulations reveal key structural changes in the C-terminus, implicating His187 in the misfolding process.
Area of Science:
- Biochemistry
- Structural Biology
- Neuroscience
Background:
- Prion diseases are linked to the misfolding of prion protein (PrP) into a pathogenic β-rich form (PrP(Sc)).
- The endocytic pathway, with its low pH environment, is a proposed site for PrP misfolding.
Purpose of the Study:
- To investigate the conformational changes of human PrP 90-231 in response to varying pH levels.
- To elucidate the role of pH in prion protein misfolding and identify key regions involved.
Main Methods:
- Constant-pH molecular dynamics simulations of human PrP 90-231.
- Simulations were conducted across a pH range of 2-7, totaling over 2 μs.
Main Results:
- A significant pH-dependent conformational change was observed, with decreased helix content and increased β-sheet content at acidic pH.
- Structural alterations primarily occurred in the C-terminus core (regions 135-155 and 185-200), not the N-terminus.
- Protonation of His187 correlated with disrupted subdomain interactions, suggesting a role in misfolding.
- A stable β-rich structure, potentially an intermediate of PrP(Sc) formation, was observed at pH 2.
Conclusions:
- Low pH environments can induce structural changes in PrP consistent with early stages of misfolding.
- His187 is a critical residue in modulating PrP structure and potentially initiating misfolding.
- Misfolding may occur prior to dimerization in the prion protein.
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