# EpiFormer: Learning Antigen-Antibody Interactions for Epitope Prediction via Geometric Deep Learning

arXiv: https://arxiv.org/abs/2606.04154 · HTML: https://mlsanity.com/paper/2606.04154/

## Key facts

- Cited by 1 papers in the map (data through 14 Oct 2026).
- Builds on 23 of its 51 references that are in the map.
- First posted on arXiv 2 Jun 2026.

## Builds on (most cited first, 23 of 23)

- [Attention Is All You Need](https://mlsanity.com/paper/1706.03762/) (2017)
- [A Simple Framework for Contrastive Learning of Visual Representations](https://mlsanity.com/paper/2002.05709/) (2020)
- [Semi-Supervised Classification with Graph Convolutional Networks](https://mlsanity.com/paper/1609.02907/) (2016)
- [Graph Attention Networks](https://mlsanity.com/paper/1710.10903/) (2017)
- [Fast Graph Representation Learning with PyTorch Geometric](https://mlsanity.com/paper/1903.02428/) (2019)
- [Modeling Relational Data with Graph Convolutional Networks](https://mlsanity.com/paper/1703.06103/) (2017)
- [E(n) Equivariant Graph Neural Networks](https://mlsanity.com/paper/2102.09844/) (2021)
- [Sigmoid-Weighted Linear Units for Neural Network Function Approximation in Reinforcement Learning](https://mlsanity.com/paper/1702.03118/) (2017)
- [Generalised Dice overlap as a deep learning loss function for highly unbalanced segmentations](https://mlsanity.com/paper/1707.03237/) (2017)
- [SE(3)-Transformers: 3D Roto-Translation Equivariant Attention Networks](https://mlsanity.com/paper/2006.10503/) (2020)
- [Learning from Protein Structure with Geometric Vector Perceptrons](https://mlsanity.com/paper/2009.01411/) (2020)
- [DiffDock: Diffusion Steps, Twists, and Turns for Molecular Docking](https://mlsanity.com/paper/2210.01776/) (2022)
- [Equiformer: Equivariant Graph Attention Transformer for 3D Atomistic Graphs](https://mlsanity.com/paper/2206.11990/) (2022)
- [EquiformerV2: Improved Equivariant Transformer for Scaling to Higher-Degree Representations](https://mlsanity.com/paper/2306.12059/) (2023)
- [Protein Representation Learning by Geometric Structure Pretraining](https://mlsanity.com/paper/2203.06125/) (2022)
- [Characterizing and overcoming the greedy nature of learning in multi-modal deep neural networks](https://mlsanity.com/paper/2202.05306/) (2022)
- [Energy-Motivated Equivariant Pretraining for 3D Molecular Graphs](https://mlsanity.com/paper/2207.08824/) (2022)
- [DiffDock-PP: Rigid Protein-Protein Docking with Diffusion Models](https://mlsanity.com/paper/2304.03889/) (2023)
- [EquiPocket: an E(3)-Equivariant Geometric Graph Neural Network for Ligand Binding Site Prediction](https://mlsanity.com/paper/2302.12177/) (2023)
- [AsEP: Benchmarking Deep Learning Methods for Antibody-specific Epitope Prediction](https://mlsanity.com/paper/2407.18184/) (2024)
- [Relation-Aware Equivariant Graph Networks for Epitope-Unknown Antibody Design and Specificity Optimization](https://mlsanity.com/paper/2501.00013/) (2024)
- [AtomSurf : Surface Representation for Learning on Protein Structures](https://mlsanity.com/paper/2309.16519/) (2023)
- [Improving Paratope and Epitope Prediction by Multi-Modal Contrastive Learning and Interaction Informativeness Estimation](https://mlsanity.com/paper/2405.20668/) (2024)

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

- [Hierarchical Federated Transfer Learning in Digital Twin-Based Vehicular Networks](https://mlsanity.com/paper/2608.11532/) (2026)

## Abstract (arXiv)

Antibodies neutralize foreign antigens by binding to specific surface regions called epitopes. Computational epitope prediction is critical for understanding immune recognition and guiding antibody engineering. However, existing methods face three fundamental challenges: antibody-aware models encode each chain independently and combine them only at a late stage, failing to capture co-dependent structural features that define binding interfaces, whereas severe class imbalance and scarcity of known antibody-antigen complexes render standard training objectives ineffective. We propose EpiFormer, a general encoder-decoder framework that addresses these challenges jointly. Our key design principle is interleaved cross-attention within GNN encoding layers, enabling bidirectional antigen-antibody information flow throughout representation learning rather than only at the output. This early-fusion principle is backbone-agnostic, providing consistent gains across GNN architectures from simple GCNs to equivariant models. We further show that sparsity-aware objectives are effective when paired with early-fusion architectures for the epitope prediction task. EpiFormer improves over the previous best method by over 40% in F1 score on standard benchmarks, demonstrating generalizability and cross-dataset transferability. Notably, EpiFormer discovers known biological principles as emergent behaviors of end-to-end training, where the learned cross-attention gates favor antigen-to-antibody information flow, consistent with the asymmetric roles of the two chains at the binding interface, and the model's preference for geometric over evolutionary features aligns with the established finding that epitope residues are not evolutionarily conserved. The source code is available at: https://github.com/mansoor181/epiformer.git