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, Hung T. Nguyen, Farkhad Maksudov, Abhinaw Kumar, Wade Zeno, Jeanne C. Stachowiak, John E. Straub, and 1 more author

Prot. Sci., 2025

Abstract bioRxiv HTML Code

The preponderance of intrinsically disordered proteins (IDPs) in the eukaryotic proteome, and their ability to interact with each other, and with folded proteins, RNA, and DNA for functional purposes, have made it important to quantitatively characterize their biophysical properties. Toward this end, we developed the transferable self-organized polymer (SOP-IDP) model to calculate the properties of several IDPs. The values of the radius of gyration (Rg) obtained from SOP-IDP simulations are in excellent agreement (correlation coefficient of 0.96) with those estimated from SAXS experiments. For AP180 and Epsin, the predicted values of the hydrodynamic radii (Rhs) are in nearly quantitative agreement with those from fluorescence correlation spectroscopy (FCS) experiments. Strikingly, the calculated SAXS profiles for 36 IDPs are also nearly superimposable on the experimental profiles. The dependence of Rg and the mean end-to-end distance (Ree) on chain length, N, follows Flory’s scaling law, Rα≈aαN^0.588 (α=g and ee), suggesting that globally IDPs behave as synthetic polymers in a good solvent. This finding depends on the solvent quality, which can be altered by changing variables such as pH and salt concentration. The values of ag and ae are 0.20 and 0.48 nm, respectively. Surprisingly, finite size corrections to scaling, expected on theoretical grounds, are negligible for Rg and Ree. In contrast, only by accounting for the finite sizes of the IDPs, the dependence of experimentally measurable Rh on N can be quantitatively explained using ν=0.588. Although Flory scaling law captures the estimates for Rg, Ree, and Rh accurately, the spread of the simulated data around the theoretical curve is suggestive of of sequence-specific features that emerge through a fine-grained analysis of the conformational ensembles using hierarchical clustering. Typically, the ensemble of conformations partitions into three distinct clusters, having different equilibrium populations and structural properties. Without any further readjustments to the parameters of the SOP-IDP model, we also obtained nearly quantitative agreement with paramagnetic relaxation enhancement (PRE) measurements for α-synuclein. The transferable SOP-IDP model sets the stage for several applications, including the study of phase separation in IDPs and interactions with nucleic acids.