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

Abstract

The conformational transition of prion protein (PrP) from a native form PrP C to a pathological isoform PrP Sc 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.

Unraveling the Molecular Mechanism of Prion H2 C-Terminus Misfolding by Metadynamics Simulations

“…Additionally, the result of secondary structure analysis proves the instability of H2 C-terminus, which fits well with the experimental results . This result is also in line with our previous work that H2 C-terminus was easily partially unfolded and was the key site for PrP misfolding …”

“…Compared to experimental methods, computational molecular dynamics (MD) simulations can provide more detailed transient structural dynamics at the atomic level and the potential transition pathways as well. For the PrP system, our group has recently investigated the pH-induced misfolding mechanism of PrP by accelerated MD simulations and found that both the H2 C-terminus and the S2–H2 loop were critical sites for PrP misfolding . Protonated H187 in the H2 C-terminus is the key inducing factor in the pH-induced PrP misfolding process.…”

“…Well-tempered metadynamics simulations of 500 ns were performed for each system. The contact number ( N C ) between residue 187 and R156, Y157, P158, and F198 (Figure b) and the average ψ angle (ψ avg ) of H2 C-terminus (Figure c) were chosen as two CVs for metadynamics simulations, since these parameters were formerly reported to be crucial for the stability and structural transition of H2 C-terminus. , Specifically, N C can directly reflect the change of interactions among related residues, , and ψ avg can be employed to monitor the secondary structure change process . This investigation allowed us to construct the FESs of the PrP misfolding process based on the structural transition of H2 C-terminus, which may provide quantitative insights into the possible implications of the H2 C-terminus related function for PrP misfolding.…”

Uncovering the Resistance Mechanism of Mycobacterium tuberculosis to Rifampicin Due to RNA Polymerase H451D/Y/R Mutations From Computational Perspective

“…Dynamic network analysis, as an effective method to extract information from the obtained molecular dynamics trajectories, has been successfully applied in protein misfolding (Zhou et al, 2019) and protein–protein interaction analysis (Sethi et al, 2009; Bai et al, 2014). Here, in order to observe the dynamic changes of the residues interaction network, 2,000 snapshots were extracted from the last 50-ns trajectory for each system.…”

Zinc-mediated conformational preselection mechanism in the allosteric control of DNA binding to the zinc transcriptional regulator (ZitR)

“…Accelerated molecular dynamics (aMD) simulations, which add a boost potential to the system’s potential and sample enhanced conformational space 21 , 22 , have been increasingly exploited to investigate long-time dynamics and infrequent conformational changes of biomacromolecules 23 – 27 . Simulations have also confirmed the effect of the ligand in MarR family 28 .…”