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Combination of Markov state models and kinetic networks for the analysis of molecular dynamics simulations of peptide folding.

Radford IH, Fersht AR, Settanni G - J Phys Chem B (2011)

Bottom Line: The trajectories have been analyzed using a Markov state model defined on the projections along two significant observables and a kinetic network approach.The kinetic network analysis served to extract the main transition state for folding of the peptide and to validate the results from the Markov state analysis.The transition state for the main folding reaction is similar to the intermediate state, although a more native like side-chain packing is observed.

View Article: PubMed Central - PubMed

Affiliation: MRC-Centre for Protein Engineering, Cambridge, UK.

ABSTRACT
Atomistic molecular dynamics simulations of the TZ1 beta-hairpin peptide have been carried out using an implicit model for the solvent. The trajectories have been analyzed using a Markov state model defined on the projections along two significant observables and a kinetic network approach. The Markov state model allowed for an unbiased identification of the metastable states of the system, and provided the basis for commitment probability calculations performed on the kinetic network. The kinetic network analysis served to extract the main transition state for folding of the peptide and to validate the results from the Markov state analysis. The combination of the two techniques allowed for a consistent and concise characterization of the dynamics of the peptide. The slowest relaxation process identified is the exchange between variably folded and denatured species, and the second slowest process is the exchange between two different subsets of the denatured state which could not be otherwise identified by simple inspection of the projected trajectory. The third slowest process is the exchange between a fully native and a partially folded intermediate state characterized by a native turn with a proximal backbone H-bond, and frayed side-chain packing and termini. The transition state for the main folding reaction is similar to the intermediate state, although a more native like side-chain packing is observed.

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Residue-specific secondary structure distribution for the states D1 (blue), D2 (green), I (yellow), N (red), and T (black) at 330 K for (a) the turn sequence, (b) extended β-sheet, (c) β-bridge structures, and (d) random coil.
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fig7: Residue-specific secondary structure distribution for the states D1 (blue), D2 (green), I (yellow), N (red), and T (black) at 330 K for (a) the turn sequence, (b) extended β-sheet, (c) β-bridge structures, and (d) random coil.

Mentions: The changes in the secondary structure content between the states along the peptide sequence were also examined. Within each of the D1, D2, I, N, and T states, the numbers of conformations with random coil, turn, extended β-sheet, or β-bridge structures were calculated as a fraction of the total number of conformations for each of the 12 residues at the three simulation temperatures. Since the changes in secondary structure between the states at each temperature are nearly identical (see Figure 6), only the 330 K data are shown in Figure 7.


Combination of Markov state models and kinetic networks for the analysis of molecular dynamics simulations of peptide folding.

Radford IH, Fersht AR, Settanni G - J Phys Chem B (2011)

Residue-specific secondary structure distribution for the states D1 (blue), D2 (green), I (yellow), N (red), and T (black) at 330 K for (a) the turn sequence, (b) extended β-sheet, (c) β-bridge structures, and (d) random coil.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3106446&req=5

fig7: Residue-specific secondary structure distribution for the states D1 (blue), D2 (green), I (yellow), N (red), and T (black) at 330 K for (a) the turn sequence, (b) extended β-sheet, (c) β-bridge structures, and (d) random coil.
Mentions: The changes in the secondary structure content between the states along the peptide sequence were also examined. Within each of the D1, D2, I, N, and T states, the numbers of conformations with random coil, turn, extended β-sheet, or β-bridge structures were calculated as a fraction of the total number of conformations for each of the 12 residues at the three simulation temperatures. Since the changes in secondary structure between the states at each temperature are nearly identical (see Figure 6), only the 330 K data are shown in Figure 7.

Bottom Line: The trajectories have been analyzed using a Markov state model defined on the projections along two significant observables and a kinetic network approach.The kinetic network analysis served to extract the main transition state for folding of the peptide and to validate the results from the Markov state analysis.The transition state for the main folding reaction is similar to the intermediate state, although a more native like side-chain packing is observed.

View Article: PubMed Central - PubMed

Affiliation: MRC-Centre for Protein Engineering, Cambridge, UK.

ABSTRACT
Atomistic molecular dynamics simulations of the TZ1 beta-hairpin peptide have been carried out using an implicit model for the solvent. The trajectories have been analyzed using a Markov state model defined on the projections along two significant observables and a kinetic network approach. The Markov state model allowed for an unbiased identification of the metastable states of the system, and provided the basis for commitment probability calculations performed on the kinetic network. The kinetic network analysis served to extract the main transition state for folding of the peptide and to validate the results from the Markov state analysis. The combination of the two techniques allowed for a consistent and concise characterization of the dynamics of the peptide. The slowest relaxation process identified is the exchange between variably folded and denatured species, and the second slowest process is the exchange between two different subsets of the denatured state which could not be otherwise identified by simple inspection of the projected trajectory. The third slowest process is the exchange between a fully native and a partially folded intermediate state characterized by a native turn with a proximal backbone H-bond, and frayed side-chain packing and termini. The transition state for the main folding reaction is similar to the intermediate state, although a more native like side-chain packing is observed.

Show MeSH