The folding mechanism and key metastable state identification of the PrP127-147 monomer studied by molecular dynamics simulations and Markov state model analysis
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Shuangyan Zhou1, Qianqian Wang, Yuwei Wang
1School of Pharmacy, Lanzhou University, Lanzhou 730000, China. hxliu@lzu.edu.cn.
Abstract:
The structural transition of prion proteins from a native α-helix (PrPC) to a misfolded β-sheet-rich conformation (PrPSc) is believed to be the main cause of a number of prion diseases in humans and animals. Understanding the molecular basis of misfolding and aggregation of prion proteins will be valuable for unveiling the etiology of prion diseases. However, due to the limitation of conventional experimental techniques and the heterogeneous property of oligomers, little is known about the molecular architecture of misfolded PrPSc and the mechanism of structural transition from PrPC to PrPSc. The prion fragment 127-147 (PrP127-147) has been reported to be a critical region for PrPSc formation in Gerstmann-Straussler-Scheinker (GSS) syndrome and thus has been used as a model for the study of prion aggregation. In the present study, we employ molecular dynamics (MD) simulation techniques to study the conformational change of this fragment that could be relevant to the PrPC-PrPSc transition. Employing extensive replica exchange molecular dynamics (REMD) and conventional MD simulations, we sample a huge number of conformations of PrP127-147. Using the Markov state model (MSM), we identify the metastable conformational states of this fragment and the kinetic network of transitions between the states. The resulting MSM reveals that disordered random-coiled conformations are the dominant structures. A key metastable folded state with typical extended β-sheet structures is identified with Pro137 being located in a turn region, consistent with a previous experimental report. Conformational analysis reveals that intrapeptide hydrophobic interaction and two key residue interactions, including Arg136-His140 and Pro137-His140, contribute a lot to the formation of ordered extended β-sheet states. However, network pathway analysis from the most populated disordered state indicates that the formation of extended β-sheet states is quite slow (at the millisecond level), as large structural rearrangement is needed from disordered states. We speculate that the formation process of the extended β-sheet folded states may represent an important event during the early formation of prion oligomers and the results of our study provide insights into the molecular details of the early stage of prion aggregation.
Insights
Misfolded prion proteins (PrPSc) cause prion diseases. Molecular dynamics simulations reveal disordered structures dominate the prion fragment 127-147, with slow transitions to β-sheet states, offering insights into early prion aggregation.
Area of Science:
- Biophysics
- Structural Biology
- Computational Neuroscience
Background:
- Prion diseases stem from the misfolding of native α-helix prion proteins (PrPC) into β-sheet-rich forms (PrPSc).
- Understanding the molecular basis of PrPSc formation and aggregation is crucial for elucidating prion disease etiology.
- Limited experimental techniques hinder the study of PrPSc molecular architecture and the PrPC-to-PrPSc transition mechanism.
Purpose of the Study:
- To investigate the conformational changes of the prion fragment 127-147 (PrP127-147), a key region for PrPSc formation.
- To elucidate the molecular mechanisms underlying the structural transition relevant to prion aggregation using computational methods.
Main Methods:
- Extensive replica exchange molecular dynamics (REMD) and conventional molecular dynamics (MD) simulations were employed to sample PrP127-147 conformations.
- Markov state modeling (MSM) was utilized to identify metastable conformational states and their transition kinetics.
Main Results:
- Disordered, random-coiled conformations were identified as the dominant structures for PrP127-147.
- A key metastable folded state with extended β-sheet structures was identified, with Pro137 in a turn region.
- Intrapeptide hydrophobic interactions and specific residue interactions (Arg136-His140, Pro137-His140) stabilize the β-sheet states.
- Transition from disordered to β-sheet states is kinetically slow, requiring significant structural rearrangement.
Conclusions:
- The formation of extended β-sheet states in PrP127-147 may represent a critical early event in prion oligomer formation.
- The study provides molecular-level insights into the initial stages of prion aggregation.
- Computational approaches like MD and MSM are valuable for studying prion protein misfolding and aggregation dynamics.