Towards All-Atom Foundation Models for Biomolecular Binding Affinity Prediction

Liang Shi, Zuobai Zhang, Huiyu Cai, Santiago Miret, Zhi Yang, Jian Tang

Keywords: Biology foundation model, biomolecular interaction prediction, representation learning

Abstract: Biomolecular interactions play a critical role in biological processes. While recent breakthroughs like AlphaFold 3 have enabled accurate modeling of biomolecular complex structures, predicting binding affinity remains challenging mainly due to limited high-quality data. Recent methods are often specialized for specific types of biomolecular interactions, limiting their generalizability. In this work, we repurpose AlphaFold 3 for representation learning to predict binding affinity, a non-trivial task that requires shifting from generative structure prediction to encoding observed geometry, simplifying the heavily conditioned trunk module, and designing a framework to jointly capture sequence and structural information. To address these challenges, we introduce the **Atom-level Diffusion Transformer (ADiT)**, which takes sequence and structure as inputs, employs a unified tokenization scheme, integrates diffusion transformers, and removes dependencies on multiple sequence alignments and templates. We pre-train three ADiT variants on the PDB dataset with a denoising objective and evaluate them across protein-ligand, drug-target, protein-protein, and antibody-antigen interactions. The model achieves state-of-the-art or competitive performance across benchmarks, scales effectively with model size, and successfully identifies wet-lab validated affinity-enhancing antibody mutations, establishing a generalizable framework for biomolecular interactions. Our open-source implementation is available at https://github.com/VectorShi/ADiT.

Primary Area: applications to physical sciences (physics, chemistry, biology, etc.)

Submission Number: 12494