TD3B: Transition-Directed Discrete Diffusion for Allosteric Binder Generation

• URL: http://arxiv.org/abs/2605.09810v1
• Date: Sun, 10 May 2026 23:17:06 GMT
• Title: TD3B: Transition-Directed Discrete Diffusion for Allosteric Binder Generation
• Abstract summary: 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.<n> TD3B combines a target-aware Direction, a soft binding-affinity gate, and amortized fine-tuning of a pre-trained discrete diffusion model, enabling targeted agonist generation decoupled from binding affinity and unattainable by equilibrium-based or inference-only guidance baselines.
• Score: 41.31786592695572
• License: http://creativecommons.org/licenses/by-nc-nd/4.0/
• 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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