Sizes, conformational fluctuations, and SAXS profiles for Intrinsically Disordered Proteins

The preponderance of Intrinsically Disordered Proteins (IDPs) in the eukaryotic proteome, and their ability to interact with each other, proteins, RNA, and DNA for functional purposes have made it important to quantitatively characterize their biophysical properties. Towards this end, we developed the transferable Self-Organized Polymer (SOP-IDP) model in order to calculate the properties of a number of IDPs. The calculated and measured radius of gyration values (Rgs) are in excellent agreement, with a correlation coefficient of 0.96. For AP180 and Epsin, the predicted and values obtained using Fluorescence Correlation Spectroscopy for the hydrodynamic radii (Rhs) are also in quantitative agreement. Strikingly, the calculated SAXS profiles for thirty six IDPs also nearly match the experiments. The dependence of Rg, the mean end-to-end distance (Re), and Rh obey the Flory scaling law, Rα ≈ aαN0.59 (α = g, e, and h), suggesting that globally IDPs behave as polymers in a good solvent. The values of ag, ae, and ah are 0.21 nm, 0.53 nm, and 0.16 nm, respectively. Surprisingly, finite size corrections to scaling, expected on theoretical grounds, for all the three quantities are negligible. Sequence dependencies, masked in ensemble properties, emerge through a fine structure analyses of the conformational ensembles using a hierarchical clustering method. Typically, the ensemble of conformations partition into three distinct clusters, with differing extent of population and structural properties. The subpopulations could dictate phase separation tendencies and association with ligands. Without any adjustments to the three parameters in the SOP-IDP model, we obtained excellent agreement with paramagnetic relaxation enhancement (PRE) measurements for α-synuclein. The transferable SOP-IDP model sets the stage for a number of promising applications, including the study of phase separation in IDPs and interactions with nucleic acids.