Test and Evaluation of <i>ff99IDPs</i> Force Field for Intrinsically Disordered Proteins

Abstract

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