The IDP-Specific Force Field ff14IDPSFF Improves the Conformer Sampling of Intrinsically Disordered Proteins

Abstract

Intrinsically disordered proteins (IDPs) or intrinsically disordered regions have not fixed tertiary structure, but play key roles in signal regulation, molecule recognition, and drug target. However it is difficult to study the structure and function of IDPs by traditional experimental methods because of their diverse conformations. Limitations of current generic protein force fields and solvent models were reported in the previous simulations of IDPs. We have also explored to overcome these limitations by developing ff99IDPs and ff14IDPs force fields to correct the dihedral distribution for eight disordered promoting residues often observed in IDPs and found encouraging improvements. Here, we extend our correction of backbone dihedral terms to all 20 naturally occurring amino acids in the IDP-specific force field (ff14IDPSFF) to further improve the quality in the modeling of IDPs. Extensive tests of seven IDPs and 14 unstructured short peptides show that the simulated Cα chemical shifts with the ff14IDPSFF force field are in quantitative agreement with those from NMR experiment and are more accurate than the base generic force field and also our previous ff14IDPs that only corrects the eight disorder-promoting amino acids. The influences of solvent models were also investigated and found to be less important. Finally our explicit solvent MD simulations further show that ff14IDPSFF can still be used to model structural and dynamical properties of two tested folded proteins, with a slightly better agreement in the loop regions for both structural and dynamical properties. These findings confirm that the newly developed IDP-specific force field ff14IDPSFF can improve the conformer sampling of intrinsically disordered proteins.

Conformation dynamics of the intrinsically disordered protein c-Myb with the ff99IDPs force field

“…19 In order to better reproduce the disordered conformation, a set of AMBER force fields ff99IDPs 20, 21 and others 22 were used, which were developed specially for IDPs with grid-based energy correction maps (CMAP) term 23, 24 to correct the dihedral of backbone for eight disordered-promotion residues of Alanine, Arginine, Glycine, Glutamine, Serine, Glutamic acid, Lysine, and Proline. By adding CMAP energy term, the Φ/Ψ distributions of the eight disorder-promoting residues have been improved with respect to the benchmark data of IDPs, while the root mean squared percentage deviation is less than 0.15% between the benchmark and the simulation 20 .…”

Secondary structures transition of tau protein with intrinsically disordered proteins specific force field

“…[50] The default cutoff distance is 8 Å for evaluating the van der Waals and direct Coulomb interactions. [52] The force fields of ff14SB, [53] ff14IDPs, [45] and ff14IDPSFF [41] were employed to handle the intramolecular interactions, respectively. [51] The long-range electrostatic interactions were evaluated by using partial Mesh Ewald (PME) method.…”

“…However, the structural basis of PHFs is still unsolved for assembly in atomic detail. [41][42][43] Force field plays a key role of MD simulations, but the validity of force field for MD simulations limits the proper sampling of IDPs. [36,38] Thus, the usage of former probes to characterize secondary structures content is limited for the studies of Tau aggregation.…”

“…Furthermore, Tau is a hydrophilic protein and belongs to the class of intrinsically disordered proteins (IDPs) without apparent ordered secondary structures detected by spectroscopy methods (CD). To overcome this defect, several generations of IDP-specific AMBER force fields such as ff99IDPs, [44] ff14IDPs, [45] and ff14IDPSFF [41] were built to improve the accurate modeling of IDPs. [39,40] Furthermore, molecular dynamics (MD) simulation is a powerful tool to investigate the dynamic ensemble of heterogeneous conformations and has referential significance to experiment for revealing the disorder-function paradigm of IDPs.…”

“…[36,38] Thus, the usage of former probes to characterize secondary structures content is limited for the studies of Tau aggregation. [41,46] Tau protein, as a highly soluble IDPs with little secondary structures, is suitable for understanding the disorderfunction relationship for IDPs with IDP-specific force fields. [41][42][43] Force field plays a key role of MD simulations, but the validity of force field for MD simulations limits the proper sampling of IDPs.…”