TD3B: Transition-Directed Discrete Diffusion for Allosteric Binder Generation

2026-05-10

AI Summary

Current structure-based approaches struggle to model the directional regulation of ligand-induced conformational transitions in proteins and cannot distinguish between agonists and antagonists. To address this limitation, this work proposes the first sequence-based generative framework that explicitly models directional state transitions to enable function-oriented design of allosteric binders, decoupling functional control from binding affinity. The method integrates a target-aware directional oracle, a soft binding-affinity gating mechanism, and an amortized fine-tuning strategy based on a pretrained discrete diffusion model. Experimental results demonstrate that the generated molecules consistently exhibit the specified agonistic or antagonistic activity, significantly outperforming existing baselines.

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.

Problem

• allosteric binder
• directional transition
• agonist vs antagonist
• GPCRs
• structure-based design

Innovation

• directional transition control
• discrete diffusion model
• allosteric binder design
• agonist/antagonist generation
• sequence-based generative modeling