Full structural ensembles of intrinsically disordered proteins from unbiased molecular dynamics simulations

Shrestha, Utsab R.; Smith, Jeremy C.; Petridis, Loukas

doi:10.1038/s42003-021-01759-1

Title: Full structural ensembles of intrinsically disordered proteins from unbiased molecular dynamics simulations

Journal Article · 22 February 2021 · Communications Biology

DOI: https://doi.org/10.1038/s42003-021-01759-1 · OSTI ID:1766885

Shrestha, Utsab R.; Smith, Jeremy C.;

Abstract Molecular dynamics (MD) simulation is widely used to complement ensemble-averaged experiments of intrinsically disordered proteins (IDPs). However, MD often suffers from limitations of inaccuracy. Here, we show that enhancing the sampling using Hamiltonian replica-exchange MD (HREMD) led to unbiased and accurate ensembles, reproducing small-angle scattering and NMR chemical shift experiments, for three IDPs of varying sequence properties using two recently optimized force fields, indicating the general applicability of HREMD for IDPs. We further demonstrate that, unlike HREMD, standard MD can reproduce experimental NMR chemical shifts, but not small-angle scattering data, suggesting chemical shifts are insufficient for testing the validity of IDP ensembles. Surprisingly, we reveal that despite differences in their sequence, the inter-chain statistics of all three IDPs are similar for short contour lengths (< 10 residues). The results suggest that the major hurdle of generating an accurate unbiased ensemble for IDPs has now been largely overcome.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1766885

Journal Information:: Communications Biology, Journal Name: Communications Biology Journal Issue: 1 Vol. 4; ISSN 2399-3642

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United Kingdom

Language:: English

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