Abstract
Experimental studies on intrinsically disordered and unfolded proteins have shown that in isolation they typically have low populations of secondary structure and exhibit distance scalings suggesting that they are at near-theta-solvent conditions. Until recently, however, all-atom force fields failed to reproduce these fundamental properties of intrinsically disordered proteins (IDPs). Recent improvements by refining against ensemble-averaged experimental observables for polypeptides in aqueous solution have addressed deficiencies including secondary structure bias, global conformational properties, and thermodynamic parameters of biophysical reactions such as folding and collapse. To date, studies utilizing these improved all-atom force fields have mostly been limited to a small set of unfolded or disordered proteins. Here, we present data generated for a diverse library of unfolded or disordered proteins using three progressively improved generations of Amber03 force fields, and we explore how global and local properties are affected by each successive change in the force field. We find that the most recent force field refinements significantly improve the agreement of the global properties such as radii of gyration and end-to-end distances with experimental estimates. However, these global properties are largely independent of the local secondary structure propensity. This result stresses the need to validate force fields with reference to a combination of experimental data providing information about both local and global structure formation.