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IDR Binder Design: Computational Design of Proteins that Bind Intrinsically Disordered Regions
Intrinsically Disordered Region (IDR) Binder Design is a general computational method for designing proteins that bind intrinsically disordered protein regions in extended conformations, with side chains fitting into complementary pockets. It was reported by Kejia Wu, David Baker and colleagues in Science in 2025 under the title "Design of intrinsically disordered region binding proteins".
Intrinsically disordered regions have no fixed fold, which makes them hard targets for conventional binder design. Many of them are involved in signaling and disease, and reagents that recognize them are scarce. Methods that rely on a stable, well-defined target surface do not carry over directly, because the target changes shape.
The authors address this by building binders that hold the disordered segment in an extended conformation, so that each residue of the target sits in a matching pocket on the binder.
Property | Detail |
|---|---|
Task | De novo design of binders for intrinsically disordered regions |
Target conformation | Diverse extended conformations |
Targets with binders | 39 structurally diverse unstructured targets, including polar ones |
Reported affinity | 100 picomolar to 100 nanomolar in 34 cases |
Specificity | Specific for intended targets in all-by-all binding experiments |
Venue | Science, 2025 |
How IDR Binder Design Works
According to the authors preprint on bioRxiv, the design pipeline has these steps:
Pocket generation: binding pockets for single amino acids and dipeptides were built by docking repeat proteins to extended peptide conformations, selecting for hydrogen bonds, and optimizing sequences with ProteinMPNN.
Backbone remodeling: pockets were resampled with parametric methods, Rosetta and RFdiffusion, and a motif diffusion approach that holds residues around key hydrogen bonds fixed performed best.
Pocket assembly: single-amino-acid pockets were combined, two to six at a time, into chimeric backbones, giving a template library that grew from 340 to 1,000 templates.
Threading and refinement: disordered target segments of 4 to 30 residues were threaded onto templates, then designed and scored with ProteinMPNN and AlphaFold2, and refined with RFdiffusion.
Experimental Results for Designed IDR Binders
The published abstract reports binders for 39 structurally diverse targets, with affinities from 100 picomolar to 100 nanomolar in 34 cases. The designs worked in cells and as detection reagents. The preprint gives further detail:
Experiment | Reported outcome |
|---|---|
Dynorphin A binders | Of 48 refined designs, 45 showed strong binding and six had Kd of 100 pM or lower by BLI |
Crystal structure of a dynorphin binder | 2.7 A resolution, interface backbone RMSD of 1.2 A to the design |
Kappa opioid receptor assay | One design had an IC50 of 50.3 nM in a cAMP assay |
Affinity capture | Binder-conjugated beads recovered about 90% of the target from buffer and blood samples |
Orthogonality | A 20 by 20 BLI matrix showed little cross-reactivity at concentrations up to 1 uM |
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Accelerating Discovery with IDR Binder Design on Tamarind Bio
Detection reagents: create binders that recognize disordered targets, which the authors show working as detection reagents.
Affinity capture: design binders for pulling a disordered protein out of complex samples such as blood.
Cell-based studies: the designs were shown to work in cells, for example antagonizing a receptor signaling response.
Multiplexed targeting: use orthogonal binders to distinguish related sequences.
How to Use IDR Binder Design on Tamarind Bio
Log in and open the tool: sign in at tamarind.bio and open IDR Binder Design.
Provide the target sequence: enter the amino acid sequence of the disordered region you want to bind, if exposed. The paper threads segments of 4 to 30 residues.
Set design parameters: choose the number of designs and any other options the interface exposes.
Run the job: submit it and wait for the designs to finish.
Download outputs: retrieve the designed binder structures and sequences.
Rank and filter: prioritize designs by the structure-prediction agreement and energy metrics described in the paper.
Validate experimentally: test several designs per target by binding assays, since the authors tested about 36 designs per target.
Things to Keep in Mind
Polar and highly flexible targets were harder early on and may need more designs to succeed.
Affinity and selectivity can trade off, and related repeat sequences can show cross-reactivity.
The approach is aimed at disordered regions with weak secondary structure and may not suit targets with strong secondary structure propensity.
Some side chain positions shifted relative to the design model in the crystal structure.
Source: Kejia Wu et al., Design of intrinsically disordered region binding proteins, Science, 2025, 389(6757), eadr8063, DOI 10.1126/science.adr8063. Preprint: 10.1101/2024.07.15.603480. No code repository is listed in the sources reviewed.