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

Area of Science:

• Biophysics
• Computational Biology
• Protein Science

Background:

• Accurate all-atom protein force fields are crucial for molecular dynamics (MD) simulations.
• Intrinsically disordered proteins (IDPs) present unique challenges for experimental structural determination.
• Current force fields may inaccurately represent the structural ensembles of IDPs, particularly those involved in liquid-liquid phase separation.

Purpose of the Study:

• To assess the accuracy of existing IDP force fields (ff99SBws, ff03ws) for disordered proteins with low amino acid sequence complexity.
• To identify and address discrepancies between simulated and experimental NMR chemical shifts in IDPs.
• To develop an improved force field that accurately captures the structural properties of IDPs.

Main Methods:

• Evaluated ff99SBws and ff03ws force fields using MD simulations of IDPs.
• Compared simulated NMR chemical shifts with experimental data.
• Introduced residue-specific modifications to the backbone torsion potential of Ser, Thr, and Gln residues in ff99SBws.
• Developed and validated the modified ff99SBws-STQ force field.

Main Results:

• Standard force fields showed exaggerated helicity in simulated IDP ensembles compared to experimental NMR data.
• The modified ff99SBws-STQ force field demonstrated improved accuracy in representing helical structure propensity.
• The ff99SBws-STQ force field accurately represented helical structures in regions with distinct sequence compositions.
• The refinement strategy successfully integrated experimental data to improve force field accuracy.

Conclusions:

• The ff99SBws-STQ force field offers a more reliable representation of IDP structural ensembles.
• This work highlights a method for refining physics-based force fields using experimental data.
• Improved force fields enhance the broader applicability of MD simulations for studying IDPs and their functions.