# Co-folding model guided by structural proteomics

arXiv: https://arxiv.org/abs/2605.26192 · HTML: https://mlsanity.com/paper/2605.26192/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 3 of its 46 references that are in the map.
- First posted on arXiv 25 May 2026.

## Builds on (most cited first, 3 of 3)

- [Score-Based Generative Modeling through Stochastic Differential Equations](https://mlsanity.com/paper/2011.13456/) (2020)
- [Diffusion Posterior Sampling for General Noisy Inverse Problems](https://mlsanity.com/paper/2209.14687/) (2022)
- [Multiscale guidance of protein structure prediction with heterogeneous cryo-EM data](https://mlsanity.com/paper/2506.04490/) (2025)

## Abstract (arXiv)

Protein structure generative models excel at predicting single protein static structures from sequence, but routinely fail to capture the correct conformational state of protein complexes, critical for protein design and induced proximity modalities such as antibodies and PROTACs. While structural proteomics techniques like Cross-Linking Mass Spectrometry (XL-MS) and Hydrogen-Deuterium Exchange (HDX-MS) offer valuable spatial and dynamic insights, integrating these sparse, heterogeneous measurements into these models remains an open challenge. Here, we bridge this gap by combining structural proteomics data with the rich biophysical priors learned by pretrained diffusion models. We introduce AIMS-Fold, an inference-time guided-diffusion framework that actively steers the generative sampling trajectory using differentiable physical potentials derived from XL-MS spatial restraints and HDX-MS solvent accessibility profiles. We demonstrate that these structural methods individually enhance predictive accuracy, and their integration yields synergistic improvement. Crucially, by leveraging these experimental restraints, AIMS-Fold achieves higher accuracy on challenging induced proximity targets than purely computational, unguided state-of-the-art models like Boltz-2. This establishes our framework as a powerful, integrative computational approach for the structure based drug design of induced proximity drugs. Evaluation code will be made publicly available upon publication.