Test and Evaluation of ff99IDPs Force Field for Intrinsically Disordered Proteins

Abstract

Over 40% eukaryotic proteomic sequences have been predicted as intrinsically disordered proteins (IDPs) or intrinsically disordered regions (IDRs) and confirmed to be associated with many diseases. However, widely used force fields could not well reproduce the conformers of IDPs. A previously ff99IDPs force field was released with CMAP energy corrections for the 8 disorder promoting residues to simulate IDPs. In order to further confirm the performance of ff99IDPs, three representative IDPs systems (arginine-rich HIV-1 Rev, aspartic proteinase inhibitor IA3, and α-Synuclein) were used to test and evaluate the simulation results. For free disordered proteins, the results show that the chemical shifts from the ff99IDPs simulations are in quantitative agreement with those from reported NMR measurements and better than those from ff99SBildn. Then, ff99IDPs can sample more clusters of disordered conformer than ff99SBildn. For structural proteins, both ff99IDPs and ff99SBildn can reproduce the conformations. In general, ff99IDPs can success in simulating the conformation of IDPs or IDRs both in bound and free states. However, relative errors could still be found at the boundaries of the scattering order-disorder promoting residues. Therefore, polarizable force fields might be one of possibility ways to further improve the performance on IDPs.

Structural Ensembles of Intrinsically Disordered Proteins Depend Strongly on Force Field: A Comparison to Experiment

“…A variety of simulation methods (MD, Monte Carlo, metadynamics, replica exchange) and different levels of representation (coarse-grained, implicit solvent, all-atom with explicit water) have been used to obtain IDP ensembles. 7,[21][22][23][24][25][26][27][28][29] There are two main challenges encountered in de novo simulations.…”

“…[23][24][25]27,28,42,[44][45][46] On the other hand, the accuracy of unfolded state and IDP structural ensembles obtained using several widely-used force fields has been called into question. [25][26][27]43,[46][47][48][49][50][51][52][53] Piana et al suggested that modern force fields, including Amber ff99sb*-ildn and CHARMM 22* in particular, produce IDP and unfolded state ensembles that are on average too compact. 48 It has also been suggested that Amber force fields systematically underestimate chain dimensions of IDPs and unfolded states.…”

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 .…”

Crystal Structure of StnA for the Biosynthesis of Antitumor Drug Streptonigrin Reveals a Unique Substrate Binding Mode

“…The Amber 12 package37 and the ff99IDPs force field383940 were used to perform MD simulations. Initial coordinates of wide type was corresponding to S185A/STM complex crystal structure using PyMOL.…”