# Conformational dynamics, binding and aggregation of intrinsically disordered proteins

> **NIH NIH R01** · ARIZONA STATE UNIVERSITY-TEMPE CAMPUS · 2021 · $273,519

## Abstract

Summary
Intrinsically disordered proteins (IDPs) make up more than 30% of eukaryotic proteomes. They carry out vital
functions in the cell, such as signaling, transcription and translation, and they regulate and control the cell
cycle. Their malfunction leads to some of the most challenging diseases, of growing concern to the US health
care system, such as cancer and neurodegeneration. The associated cost of these diseases are some of the
highest and fastest growing in the US. IDPs also play a key role in the replication and spreading of viral
pathogens. In order to function properly IDPs must (i) bind efficiently to specific binding partners; and (ii) avoid
pathological aggregation. A molecular level understanding of how IDP sequences encode for these two
processes, and how mutations and stress conditions in cells can affect them, will significantly advance our
understanding and ability to treat and prevent such diseases.
Major experimental efforts are currently focused on: (i) resolving the structural ensembles of IDPs and the
binding mechanism (IDP structure/function); or (ii) resolving the mechanisms of IDP aggregation into IDP
aggregation into specific amyloid aggregates (IDP malfunction). Here we propose a radically different, physical
chemistry approach in which we study the effect of IDP conformational dynamics on the binding mechanism;
and the quantitative relation between IDP phase separation and aggregation. We will do so by using high
resolution experimental techniques and methods developed in our lab, along with the multiscale simulations.
Because most IDPs bind through coupled folding and binding, their conformational dynamics is expected to
greatly affect the binding mechanism. Our approach of incorporating IDP conformational dynamics in binding
studies will provide a key missing link to understand IDP functional binding.
Our proposed study builds on the recent characterization of the binding mechanism of a group of IDPs, and
focuses on studying 1) the effect of conformational dynamics on binding; and 2) the physiological process of
liquid phase-separation and its link to pathological aggregation. We will combine different high resolution
experimental techniques -including nanosecond laser pump spectroscopy- with molecular simulations to
characterize IDP structure and dynamics. Novel methods will be used to quantify liquid phase-separation of
IDPs. Results from Aim I: Test our hypothesis by comparing IDP dynamics for different binding
scenarios; Aim II: Modulating the binding mechanism by perturbing the sequence and solvent, and Aim
III: Quantify the effect of a disease mutation on the conformational dynamics, phase separation and
aggregation of FUS_LC; will have direct impact on the molecular understanding IDPs implicated in ovarian
and breast cancer, in the replication of paramoxyviruses and in amyotrophic lateral sclerosis and
frontotemporal dementia. These results have the potential of transforming our way of viewing coupled fo...

## Key facts

- **NIH application ID:** 10252835
- **Project number:** 5R01GM120537-05
- **Recipient organization:** ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
- **Principal Investigator:** Sara M. Vaiana
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $273,519
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10252835

## Citation

> US National Institutes of Health, RePORTER application 10252835, Conformational dynamics, binding and aggregation of intrinsically disordered proteins (5R01GM120537-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10252835. Licensed CC0.

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