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arXiv · 2605.09810

TD3B: Transition-Directed Discrete Diffusion for Allosteric Binder Generation

Hanqun Cao·Aastha Pal·Sophia Tang·Yinuo Zhang·Jingjie Zhang·Pheng Ann Heng·Pranam Chatterjee
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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.

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Hanqun Cao, Aastha Pal, Sophia Tang, Yinuo Zhang, Jingjie Zhang, Pheng Ann Heng, Pranam Chatterjee. 2026-05-10. TD3B: Transition-Directed Discrete Diffusion for Allosteric Binder Generation. https://arxiv.org/abs/2605.09810

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