# AlloGen: Conformation-Selective Binder Generation with Differential State Scoring

arXiv: https://arxiv.org/abs/2606.05474 · HTML: https://mlsanity.com/paper/2606.05474/

## Key facts

- Cited by 1 papers in the map (data through 14 Oct 2026).
- Builds on 12 of its 48 references that are in the map.
- First posted on arXiv 3 Jun 2026.

## Builds on (most cited first, 12 of 12)

- [Attention Is All You Need](https://mlsanity.com/paper/1706.03762/) (2017)
- [Score-Based Generative Modeling through Stochastic Differential Equations](https://mlsanity.com/paper/2011.13456/) (2020)
- [Diffusion Models Beat GANs on Image Synthesis](https://mlsanity.com/paper/2105.05233/) (2021)
- [Representation Learning with Contrastive Predictive Coding](https://mlsanity.com/paper/1807.03748/) (2018)
- [Practical and Asymptotically Exact Conditional Sampling in Diffusion Models](https://mlsanity.com/paper/2306.17775/) (2023)
- [AlphaFold Meets Flow Matching for Generating Protein Ensembles](https://mlsanity.com/paper/2402.04845/) (2024)
- [PepTune: De Novo Generation of Therapeutic Peptides with Multi-Objective-Guided Discrete Diffusion](https://mlsanity.com/paper/2412.17780/) (2024)
- [Scaling Atomistic Protein Binder Design with Generative Pretraining and Test-Time Compute](https://mlsanity.com/paper/2603.27950/) (2026)
- [TR2-D2: Tree Search Guided Trajectory-Aware Fine-Tuning for Discrete Diffusion](https://mlsanity.com/paper/2509.25171/) (2025)
- [AReUReDi: Annealed Rectified Updates for Refining Discrete Flows with Multi-Objective Guidance](https://mlsanity.com/paper/2510.00352/) (2025)
- [PPDiff: Diffusing in Hybrid Sequence-Structure Space for Protein-Protein Complex Design](https://mlsanity.com/paper/2506.11420/) (2025)
- [TD3B: Transition-Directed Discrete Diffusion for Allosteric Binder Generation](https://mlsanity.com/paper/2605.09810/) (2026)

## Built on by (most cited first, 1 of 1)

- [Ensemble-Conditioned Molecular Design](https://mlsanity.com/paper/2609.15077/) (2026)

## Abstract (arXiv)

Protein binder design has largely optimized for affinity alone, leaving conformational selectivity unaddressed: for allosteric targets such as kinases, nuclear receptors, and GPCRs, a binder that engages both active and inactive states provides no functional specificity regardless of how tightly it binds. We introduce AlloGen, a modular framework that decouples backbone generation from a learned state-selectivity scorer Qθ, an SE(3)-invariant interface graph transformer trained via a two-phase curriculum that first learns interface geometry before imposing conformational discrimination. Because Qθ is fully differentiable and generator-agnostic, it integrates with any backbone generator as a passive reranker or an active gradient-based guide without retraining. Across a diverse benchmark of proteins spanning multiple families and conformational mechanisms, AlloGen consistently identifies binders that preferentially recognize desired structural states while rejecting alternative conformations. Experimental validation on calmodulin further demonstrates that these computational selectivity signals translate to physical molecules, yielding de novo peptides that bind the desired holo conformation while exhibiting no detectable binding to the apo state. Together, these results establish conformational selectivity as a learnable property and provide a general framework for state-selective protein binder design.