Recent Force Field Strategies for Intrinsically Disordered Proteins

Abstract

Intrinsically disordered proteins (IDPs) are widely distributed across eukaryotic cells, playing important roles in molecular recognition, molecular assembly, post-translational modification, and other biological processes. IDPs are also associated with many diseases such as cancers, cardiovascular diseases, and neurodegenerative diseases. Due to their structural flexibility, conventional experimental methods cannot reliably capture their heterogeneous structures. Molecular dynamics simulation becomes an important complementary tool to quantify IDP structures. This review covers recent force field strategies proposed for more accurate molecular dynamics simulations of IDPs. The strategies include adjusting dihedral parameters, adding grid-based energy correction map (CMAP) parameters, refining protein-water interactions, and others. Different force fields were found to perform well on specific observables of specific IDPs but also are limited in reproducing all available experimental observables consistently for all tested IDPs. We conclude the review with perspective areas for improvements for future force fields for IDPs.

Keywords: AMBER; CHARMM; CMAP; Dihedral parameters; Force field; GROMOS; Intrinsically disordered proteins; Molecular simulations; OPSL-AA.

Figure 1.

Comparison of ³J_HNHα couplings, chemical shift, and Rg between multiple-trajectory and REMD simulations. (a) Residual ³J_HNHα couplings. (b) Correlation of calculated ³J_HNHα couplings between multiple-trajectory and REMD simulations. (c) Residual chemical shifts of Cα atoms. (d) Correlation of calculated chemical shifts of Cα atoms between multiple-trajectory and REMD simulations. (e) Probability distribution of Rg from the simulated ensembles of Aβ42 generated by multiple-trajectory and REMD simulations. The range of experimental Rg is marked by two dash lines. The averaged Rg values from both simulation methods are marked by the solid lines and are labeled with the same colors of corresponding simulation methods.