TD3B: Transition-Directed Discrete Diffusion for Allosteric Binder Generation

TL;DR

TD3B is a novel sequence-based generative framework that designs allosteric protein binders with specified agonist or antagonist behavior by controlling transition directionality.

Contribution

It introduces a transition-directed diffusion model that enables targeted design of functional protein binders with specified activity types.

Findings

Successfully generates allosteric binders with desired functional directionality.

Decouples activity type from binding affinity in design process.

Achieves targeted agonist and antagonist generation beyond equilibrium-based methods.

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.