# Enhancing Protein-Protein Interaction Prediction with Hierarchical Motif-based Multimodal Protein Embedding

arXiv: https://arxiv.org/abs/2606.02629 · HTML: https://mlsanity.com/paper/2606.02629/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 12 of its 56 references that are in the map.
- First posted on arXiv 30 May 2026.

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

- [How Powerful are Graph Neural Networks?](https://mlsanity.com/paper/1810.00826/) (2018)
- [A Comprehensive Survey on Graph Neural Networks](https://mlsanity.com/paper/1901.00596/) (2019)
- [Deep Modular Co-Attention Networks for Visual Question Answering](https://mlsanity.com/paper/1906.10770/) (2019)
- [Hierarchical Question-Image Co-Attention for Visual Question Answering](https://mlsanity.com/paper/1606.00061/) (2016)
- [Protein Representation Learning by Geometric Structure Pretraining](https://mlsanity.com/paper/2203.06125/) (2022)
- [ProtST: Multi-Modality Learning of Protein Sequences and Biomedical Texts](https://mlsanity.com/paper/2301.12040/) (2023)
- [OntoProtein: Protein Pretraining With Gene Ontology Embedding](https://mlsanity.com/paper/2201.11147/) (2022)
- [Learning Unknown from Correlations: Graph Neural Network for Inter-novel-protein Interaction Prediction](https://mlsanity.com/paper/2105.06709/) (2021)
- [MAPE-PPI: Towards Effective and Efficient Protein-Protein Interaction Prediction via Microenvironment-Aware Protein Embedding](https://mlsanity.com/paper/2402.14391/) (2024)
- [SemiGNN-PPI: Self-Ensembling Multi-Graph Neural Network for Efficient and Generalizable Protein-Protein Interaction Prediction](https://mlsanity.com/paper/2305.08316/) (2023)
- [Computational Protein Science in the Era of Large Language Models (LLMs)](https://mlsanity.com/paper/2501.10282/) (2025)
- [Revealing data leakage in protein interaction benchmarks](https://mlsanity.com/paper/2404.10457/) (2024)

## Abstract (arXiv)

Protein-protein interactions (PPIs) are essential for many biological processes. However, existing PPI prediction approaches suffer from two major limitations: they overlook the hierarchical organization of proteins, particularly meso-scale motifs that critically regulate PPIs, and fail to effectively integrate sequence, structure, and function modalities. To address these limitations, we propose MMM-PPI, a Hierarchical Motif-based Multi-Modal protein Encoder for PPI Prediction that constructs PPI embeddings in a bottom-up multi-modal manner across three scales. At the micro-scale, we encode three modal residue features; at the meso-scale, a novel multimodal motif encoder aggregates residues into spatially-informed motif embeddings; at the macro-scale, a multimodal protein encoder integrates motifs into protein embeddings by jointly modeling motif importance and inter-modal correlations. The pre-trained encoder can be used off-the-shelf for large-scale PPI prediction. Extensive experiments on multiple PPI datasets show that MMM-PPI outperforms state-of-the-art multi-label PPI prediction models, particularly under challenging data partitions and limited data scenarios. Codes are in https://github.com/yzf-code/MMM-PPI.