Systematic Differences between Current Molecular Dynamics Force Fields To Represent Local Properties of Intrinsically Disordered Proteins

The prevalence of intrinsically disordered proteins (IDPs) and protein regions in structural biology has prompted the recent development of molecular dynamics (MD) force fields for the more realistic representations of such systems. Using experimental nuclear magnetic resonance backbone scalar (3)J-coupling constants of the intrinsically disordered proteins alpha-synuclein and amyloid-beta in their native aqueous environment as a metric, we compare the performance of four recent MD force fields, namely, AMBER ff14SB, CHARMM C36m, AMBER ff99SB-disp, and AMBER ff99SBnmr2, by partitioning the polypeptides into an overlapping series of heptapeptides for which a cumulative total of 276 mu s MD simulations were performed. The results show substantial differences between the different force fields at the individual residue level. Except for ff99SBnmr2, the force fields systematically underestimate the scalar (3)J(H-N ,H alpha)-couplings due to an underrepresentation of beta-conformations and an overrepresentation of either alpha- or PPII conformations. The study demonstrates that the incorporation of coil library information in modern MD force fields, as shown here for ff99SBnmr2, provides substantially improved performance and more realistic sampling of the local backbone dihedral angles of IDPs as reflected by the good accuracy of the computed scalar (3)J(H-N,H alpha)-couplings with less than 0.5 Hz error. Such force fields will enable a better understanding of how structural dynamics and thermodynamics influence the IDP function. Although the methodology based on heptapeptides used here does not allow the assessment of potential intramolecular long-range interactions, its computational affordability permits well-converged simulations that can be easily parallelized. This should make the quantitative validation of intrinsic disorder observed in MD simulations of polypeptides with experimental scalar J-couplings widely applicable.

Automated summary

This study compared the performance of four recent molecular dynamics force fields on simulating intrinsically disordered proteins, revealing substantial differences between these force fields at the individual residue level. The study highlighted limitations of current force fields and showed that incorporating coil library information, as demonstrated by ff99SBnmr2, can significantly improve performance and sampling realism.