# Calculating Ensembles of Discrete Dynamic Complexes and Condensed States of Intrinsically Disordered Proteins

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2023 · $325,860

## Abstract

The traditional structure-function paradigm has provided significant insights for well-folded proteins in which
structures can be easily and rapidly revealed by X-ray crystallography beamlines and NMR. However
approximately one third of the human proteome are comprised of intrinsically disordered proteins and regions
that do not adopt a dominant well-folded structure, and therefore remain “unseen” by traditional structural
biology methods. Current experimental and computational approaches to structural descriptions of disordered
proteins, while often valuable, still lack predictive power, particularly for dynamic complexes of IDPs, as well as
lack of insight into the relationships between IDP structural ensembles and function. We made significant
progress in the last grant cycle in the following four directions: (1) Generating and quantifying the utility of
experimental data types for IDP monomer ensembles; (2) Applying atomistic and coarse-grained physical
models and machine learned sampling methods for generating monomer ensembles; (3) Advancing new
Bayesian models for IDP monomer ensemble selection; (4) development of highly novel machine learning (ML)
methodology for ensemble generation and selection; (5) Creating software and monomer ensemble data and
placing them in the hands of practitioners. Many of these results serve as preliminary studies for this renewal
and are described in more detail in proposed research. But to fully address the biological activity of IDPs we
propose to adapt these computational methods further and develop new integrative biology tools that will be
more selective for dynamic associations of IDPs within both discrete dynamic complexes and biological
condensates and for post-translational modifications (PTMs) that create relevant IDP functional states. Building
on strong preliminary data from our experimental collaborators, we will record NMR, SAXS and single molecule
fluorescence data on phosphorylated and non-phosphorylated 4E-binding protein 2 (np-4E-BP2, 5p-4E-BP2)
and its dynamic complex with the eukaryotic translation initiation factor (eIF4E); tropoelastin and mixed and
condensed-phase elastin fragments; and mixed and condensed-phase CAPRIN1 C-terminal IDR, including novel
NMR experiments that probe electrostatic potentials (ESPs), 3-color smFRET, and fluorescence correlation
spectroscopy (FCS). These studies will illuminate mechanisms of translational regulation and elasticity, and
provide insights into pathological states, including autism spectrum disorder and cardiovascular disease.

## Key facts

- **NIH application ID:** 10607371
- **Project number:** 2R01GM127627-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Teresa L. Head-Gordon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $325,860
- **Award type:** 2
- **Project period:** 2018-05-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10607371

## Citation

> US National Institutes of Health, RePORTER application 10607371, Calculating Ensembles of Discrete Dynamic Complexes and Condensed States of Intrinsically Disordered Proteins (2R01GM127627-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10607371. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*