Markovian Timescales of Intramolecular Disulfide Pairing in Cyclotides
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2025
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| _version_ | 1867008317909368832 |
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| author | Jayapriya Venkatesan Durba Roy |
| author_facet | Jayapriya Venkatesan Durba Roy Jayapriya Venkatesan Durba Roy |
| collection | Wiley Open Access |
| contents | Markovian Timescales of Intramolecular Disulfide Pairing in Cyclotides Jayapriya Venkatesan Durba Roy Proteins: Structure, Function, and Bioinformatics ABSTRACT Kinetics of intramolecular disulphide pairing in a six‐cysteine containing plant toxin peptide cycloviolacin O1 (CyO1) having a cyclic backbone and a cyclic cystine knot (CCK) is studied using a Hidden Markov Model (HMM) created from molecular dynamics simulation trajectories. Starting from a fully reduced form of CyO1 (peptide‐ D ), the kinetic model is created to track the peptide's evolution to a native ‐like state (peptide‐ N ) where all three correct pairs of S‐S linkages are most likely to be observed. The structural evolution and fluctuation of peptide‐ D through many partially folded S‐S intermediates and the associated propensity, along with the timescale of formation of a single or simultaneously two or three S‐S pairs, is studied using this Markov chain. The phenomenon of intramolecular S‐S pairing, as observed in proteins and peptides, is fast, with a computed rate constant of ~10 6 s −1 in line with experimental observations in the bacterial disulphide bond redox protein DsbD. Rate networks and transition path theory analysis are used to find the most probable pathway for peptide‐ D to evolve into peptide‐ N . 10.1002/prot.70041 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| doi_str_mv | 10.1002/prot.70041 |
| format | Artículo Open Access |
| id | wiley_oa_10_1002_prot_70041 |
| institution | Wiley Open Access |
| license_str_mv | http://onlinelibrary.wiley.com/termsAndConditions#vor |
| publishDate | 2025 |
| publisher | Wiley |
| record_format | wiley_oa |
| spellingShingle | Markovian Timescales of Intramolecular Disulfide Pairing in Cyclotides Jayapriya Venkatesan Durba Roy Proteins: Structure, Function, and Bioinformatics Markovian Timescales of Intramolecular Disulfide Pairing in Cyclotides Jayapriya Venkatesan Durba Roy Proteins: Structure, Function, and Bioinformatics ABSTRACT Kinetics of intramolecular disulphide pairing in a six‐cysteine containing plant toxin peptide cycloviolacin O1 (CyO1) having a cyclic backbone and a cyclic cystine knot (CCK) is studied using a Hidden Markov Model (HMM) created from molecular dynamics simulation trajectories. Starting from a fully reduced form of CyO1 (peptide‐ D ), the kinetic model is created to track the peptide's evolution to a native ‐like state (peptide‐ N ) where all three correct pairs of S‐S linkages are most likely to be observed. The structural evolution and fluctuation of peptide‐ D through many partially folded S‐S intermediates and the associated propensity, along with the timescale of formation of a single or simultaneously two or three S‐S pairs, is studied using this Markov chain. The phenomenon of intramolecular S‐S pairing, as observed in proteins and peptides, is fast, with a computed rate constant of ~10 6 s −1 in line with experimental observations in the bacterial disulphide bond redox protein DsbD. Rate networks and transition path theory analysis are used to find the most probable pathway for peptide‐ D to evolve into peptide‐ N . 10.1002/prot.70041 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| title | Markovian Timescales of Intramolecular Disulfide Pairing in Cyclotides |
| topic | Proteins: Structure, Function, and Bioinformatics |
| url | https://onlinelibrary.wiley.com/doi/10.1002/prot.70041 |