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Refining All-Atom Protein Force Fields for Polar-Rich, Prion-like, Low-Complexity Intrinsically Disordered Proteins

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Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Phys. Chem. B 2020, 124, 43, 9505-9512
    B: Biophysics; Physical Chemistry of Biological Systems and Biomolecules

    Refining All-Atom Protein Force Fields for Polar-Rich, Prion-like, Low-Complexity Intrinsically Disordered Proteins
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    The Journal of Physical Chemistry B

    Cite this: J. Phys. Chem. B 2020, 124, 43, 9505–9512
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    https://doi.org/10.1021/acs.jpcb.0c07545
    Published October 20, 2020
    Copyright © 2020 American Chemical Society
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    Abstract

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    Significant efforts in the past decade have given us highly accurate all-atom protein force fields for molecular dynamics (MD) simulations of folded and disordered proteins. These simulations, complemented with experimental data, provide new insights into molecular interactions that underlie the physical properties of proteins, especially for intrinsically disordered proteins (IDPs) for which defining the heterogeneous structural ensemble is hugely challenging by experiments alone. Consequently, the accuracy of these protein force fields is of utmost importance to ensure reliable simulated conformational data. Here, we first assess the accuracy of current state-of-the-art force fields for IDPs (ff99SBws and ff03ws) applied to disordered proteins of low amino acid sequence complexity that can undergo liquid–liquid phase separation. On the basis of a detailed comparison of NMR chemical shifts between simulation and experiment on several IDPs, we find that regions surrounding specific polar residues result in simulated ensembles with exaggerated helicity when compared to experiment. To resolve this discrepancy, we introduce residue-specific modifications to the backbone torsion potential of three residues (Ser, Thr, and Gln) in the ff99SBws force field. The modified force field, ff99SBws-STQ, provides a more accurate representation of helical structure propensity in these LC domains without compromising faithful representation of helicity in a region with distinct sequence composition. Our refinement strategy also suggests a path forward for integrating experimental data in the assessment of residue-specific deficiencies in the current physics-based force fields and improves these force fields further for their broader applicability.

    Copyright © 2020 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jpcb.0c07545.

    • List of all simulations performed; comparison between ff99SBws-STQ (this study) and ff99SB-disp from Robustelli et al.; (33) contact propensities and radius of gyration in simulation performed with ff99SBws and ff99SBws-STQ; DSSP secondary structure as a function of simulation time for each de-multiplexed replica of simulation performed with ff99SBws-STQ; fraction helix of (AAQAA)3 with ff99SBws and ff99SBws-STQ compared to NMR experimental data (PDF)

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    The Journal of Physical Chemistry B

    Cite this: J. Phys. Chem. B 2020, 124, 43, 9505–9512
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jpcb.0c07545
    Published October 20, 2020
    Copyright © 2020 American Chemical Society
    Request reuse permissions

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