TD3B: Transition-Directed Discrete Diffusion for Allosteric Binder Generation

Hanqun Cao, Aastha Pal, Sophia Tang, Yinuo Zhang, Jingjie Zhang, Pheng-Ann Heng, Pranam Chatterjee

Keywords: Generative modeling, discrete diffusion, molecular design, protein-ligand interactions, functional biomolecular design

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.

Submission Number: 19