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Markovian Timescales of Intramolecular Disulfide Pairing in Cyclotides
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DOI：10.1002/prot.70041.png)
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Abstract
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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 ~106 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.
Keywords:
cyclotides
disulfide bonds
Markov state model
molecular dynamics
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