| title | TD3B: Transition-Directed Discrete Diffusion for Allosteric Binder Generation |
|---|---|
| authors | Hanqun Cao, Aastha Pal, Sophia Tang, Yinuo Zhang, Jingjie Zhang, Pheng Ann Heng, Pranam Chatterjee |
| date | 2026-05-10 |
| venue | arXiv (preprint, not peer reviewed) |
| id | arXiv:2605.09810 |
| affiliation | Programmable Biology Group |
| upvotes | 1 (Hugging Face Daily Papers, 2026-11-01) |
| links | abs pdf hf |
| abstract | Protein function is often controlled by ligands that bias the direction of state transitions, such as agonists and antagonists, rather than stabilizing a single conformation. This is especially important for clinically relevant G protein-coupled receptors (GPCRs), where therapeutic efficacy depends on functional directionality. Structure-based design methods optimize binding to static conformations and cannot represent non-reversible, directional effects or systematically distinguish agonist from antagonist behavior. To address this gap, we introduce Transition-Directed Discrete Diffusion for Allosteric Binder Design (TD3B), a sequence-based generative framework that designs binders with specified agonist or antagonist behavior via a directional transition control objective. TD3B combines a target-aware Direction Oracle, a soft binding-affinity gate, and amortized fine-tuning of a pre-trained discrete diffusion model, enabling targeted agonist and antagonist generation decoupled from binding affinity and unattainable by equilibrium-based or inference-only guidance baselines. The code and checkpoints are available at https://huggingface.co/ChatterjeeLab/TD3B. |
cite
@misc{cao2026td,
title={TD3B: Transition-Directed Discrete Diffusion for Allosteric Binder Generation},
author={Hanqun Cao and Aastha Pal and Sophia Tang and Yinuo Zhang and Jingjie Zhang and Pheng Ann Heng and Pranam Chatterjee},
year={2026},
eprint={2605.09810},
archivePrefix={arXiv},
url={https://arxiv.org/abs/2605.09810}
}