intrinsically disordered proteins

Intrinsically disordered proteins (IDPs) are a fascinating class of proteins that are characterized by their lack of a fixed, ordered structure. Unlike the classical paradigm of protein folding, IDPs exhibit high structural flexibility, allowing them to interact with multiple binding partners and assume a variety of conformations. This heterogeneity of their structural ensemble is a fundamental characteristic of IDPs and is essential for their diverse range of functions in cellular processes such as signaling, regulation, and molecular recognition. Indeed, many IDPs are involved in disease processes, and their dysfunction has been implicated in a range of disorders, including neurodegenerative diseases, cancer, and viral infections.

We have developed a computational model to quantitatively simulate IDP structural ensemble. Our simulations reproduced in excellent quality many structural aspects–including SAXS profiles (and thus the radius of gyration R_g), and NMR paramagnetic relaxation enhancement–of a diverse set of IDPs of different lengths and sequences. Simulations revealed that IDPs in general behave globally like self-avoiding random walk polymers, and the sequence-dependent features only emerge by careful analyses of the ensemble.

publications

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

Mauro L. Mugnai, Debayan Chakraborty, Abhinaw Kumar, Hung T. Nguyen, Wade Zeno, Jeanne C. Stachowiak, John E. Straub, and D. Thirumalai

bioRxiv, 2023

Abstract bioRxiv Code

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 ≈ ααN0.59 (α = g, e, and h), suggesting that globally IDPs behave as polymers in a good solvent. The values of αg, αe, and αh 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.