Conformational sampling of intrinsically disordered peptides by enhanced sampling methods

Abstract

The aim of this study was to explore the conformational equilibrium of four cyclic hormone peptides in order to investigate to what extent the bound conformational state can be observed from the solution phase simulations. The studied cyclic peptides share the same structural motif of a six membered ring closed by disulphide bridge between the cysteine residues. They also belong to the class of intrinsically disordered peptides known to exist in an equilibrium of different conformations. Elucidating their conformational ensemble using traditional experimental techniques has proven hard due to the fast interconversion between conformational states, and thus molecular dynamics simulation may help in providing a detailed picture of the peptide’s conformational ensemble.

However, conventional molecular dynamics simulation are limited by the long time scale required to observe many conformational motions. Therefore in this work Replica Exchange techniques were applied to test the rate of convergence in conformational sampling. Moreover, to predict the conformational equilibrium of the peptides, a combination of results from enhanced sampling methods, DFT calculations and NMR experiments was used. It was found that calculated chemical shifts weighted by the ensemble populations of each conformational state were better able to reproduce the experimental chemical shift data, over and above any single peptide conformation. This result supports the use of enhanced sampling molecular dynamics computer simulations to study intrinsically disordered peptides.

The knowledge of the conformational equilibrium and the relative populations of the unbound states of the peptides obtained using this approach may help in predicting the structural and functional roles of the bound state peptide. Another purpose of this work was also to check the extent to which a difference in peptide sequence may contribute to their functional diversity. Finally, the performance of the Replica Exchange simulations was compared, indicating that Solute Tempering is to be preferred over temperature Replica Exchange for reasons of computational efficiency.

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Identifiers

ORCID for Jonathan W. Essex: orcid.org/0000-0003-2639-2746

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