PH-Induced Misfolding Mechanism of Prion Protein: Insights from Microsecond-Accelerated Molecular Dynamics Simulations

Shuangyan Zhou, Danfeng Shi, Xuewei Liu, Xiaojun Yao, Lin Tai Da, Huanxiang Liu

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)


The conformational transition of prion protein (PrP) from a native form PrPC to a pathological isoform PrPSc is the main cause of a number of prion diseases in human and animals. Thus, understanding the molecular basis of conformational transition of PrP will be valuable for unveiling the etiology of PrP-related diseases. Here, to explore the potential misfolding mechanism of PrP under the acidic condition, which is known to promote PrP misfolding and trigger its aggregation, the conventional and accelerated molecular dynamics (MD) simulations combined with the Markov state model (MSM) analysis were performed. The conventional MD simulations reveal that, at an acidic pH, the globular domain of PrP is partially unfolded, particularly for the α2 C-terminus. Structural analysis of the key macrostates obtained by MSM indicates that the α2 C-terminus and the β2-α2 loop may serve as important sites for the pH-induced PrP misfolding. Meanwhile, the α1 may also participate in the pH-induced structural conversion by moving away from the α2-α3 subdomain. Notably, dynamical network analysis of the key metastable states indicates that the protonated H187 weakens the interactions between the α2 C-terminus, α1-β2 loop, and α2-α3 loop, leading these domains, especially the α2 C-terminus, to become unstable and to begin to misfold. Therefore, the α2 C-terminus plays a key role in the PrP misfolding process and serves as a potential site for drug targeting. Overall, our findings can deepen the understanding of the pathogenesis related to PrP and provide useful guidance for the future drug discovery.

Original languageEnglish
Pages (from-to)2718-2729
Number of pages12
JournalACS Chemical Neuroscience
Issue number6
Publication statusPublished - 19 Jun 2019
Externally publishedYes


  • Markov state model
  • Prion
  • low pH
  • misfolding
  • molecular dynamics simulation


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