# Multiscale Characterization of a Unique Class of Duplex, Multivalent IDP systems

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $442,422

## Abstract

Summary
A wide variety of subcellular complexes are composed of one or more intrinsically disordered proteins (IDPs)
that are multivalent, flexible, and characterized by dynamic, reversible binding of diverse partner proteins. A
common but understudied type of multivalent IDP assembly exhibits a unique duplex topology, characterized by
parallel alignment of two IDP chains reversibly cross-linked by the ubiquitous LC8 hub protein, where the IDPs
allosterically enhance affinity for additional bivalent ligands. These duplexes can serve as a girder-like element
in large complexes, act as sensors, and facilitate or `template' the formation of large supra-molecular assemblies
(such as the dynein motor and nucleopore complex). Key features of these systems were identified in MPI
Barbar's lab, but studies of the structural and biochemical basis for this wide range of functionalities are
challenged by the diversity, internal mobility, and heterogeneity of the complexes formed.
This proposal will significantly advance our understanding of the molecular underpinnings of multivalent LC8
complex assemblies, by integrating an array of novel and existing methods of computational modeling - such as
weighted-ensemble molecular dynamics simulation - with experiments including isothermal titration calorimetry
(ITC) and surface plasmon resonance (SPR), and structural characterization such as nuclear magnetic
resonance (NMR), electron microscopy (EM), and native mass spectrometry (native MS). These techniques
were selected to address critical unanswered questions in the field: How much conformational and compositional
heterogeneity is intrinsic to these reversibly assembled duplexes, and how do they avoid a disordered state?
How does LC8 concentration, which is tightly controlled by the cell, modulate the heterogeneity? What do the
allosteric effects and associated mechanistic pathways indicate about regulation of the duplexes? What
differences are observed among duplex systems optimized for architectural vs. complex-scaffolding vs. sensing
roles? To address these questions, three largely independent aims will probe the ensemble thermodynamics
via ITC and theory dissecting species populations, the conformational ensemble via EM and theory from whole
complex- to atomistic-scale, and finally the atomistic basis of kinetic and cooperative behavior via simulations
and kinetics measurements.
The efforts will be guided by an experienced biophysics team with a wide-range of complementary expertise who
have been collaborating for several years - experts in theoretical biophysics (Zuckerman, MPI); in LC8 structural
biology, ITC and NMR (Barbar, MPI); in electron microscopy (Reichow, Co-I); and in native MS (Prell, Co-I). Our
track record of pioneering work on structure-function relations of LC8, success in both producing useful protein
constructs and handling these complex and partially disordered proteins, and the team's expertise in the battery
of computational, structural,...

## Key facts

- **NIH application ID:** 10198490
- **Project number:** 1R01GM141733-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** ELISAR J BARBAR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $442,422
- **Award type:** 1
- **Project period:** 2021-08-03 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10198490

## Citation

> US National Institutes of Health, RePORTER application 10198490, Multiscale Characterization of a Unique Class of Duplex, Multivalent IDP systems (1R01GM141733-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10198490. Licensed CC0.

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