# Inferred global dense residue transition graphs from primary structure sequences enable protein interaction prediction via directed graph convolutional neural networks

arXiv: https://arxiv.org/abs/2510.14139 · HTML: https://mlsanity.com/paper/2510.14139/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 14 of its 37 references that are in the map.
- First posted on arXiv 15 Oct 2025.

## Builds on (most cited first, 14 of 14)

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- [Graph Attention Networks](https://mlsanity.com/paper/1710.10903/) (2017)
- [Inductive Representation Learning on Large Graphs](https://mlsanity.com/paper/1706.02216/) (2017)
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- [Learning Phrase Representations using RNN Encoder-Decoder for Statistical Machine Translation](https://mlsanity.com/paper/1406.1078/) (2014)
- [Distributed Representations of Words and Phrases and their Compositionality](https://mlsanity.com/paper/1310.4546/) (2013)
- [BioBERT: a pre-trained biomedical language representation model for biomedical text mining](https://mlsanity.com/paper/1901.08746/) (2019)
- [Cluster-GCN: An Efficient Algorithm for Training Deep and Large Graph Convolutional Networks](https://mlsanity.com/paper/1905.07953/) (2019)
- [ProtTrans: Towards Cracking the Language of Life's Code Through Self-Supervised Deep Learning and High Performance Computing](https://mlsanity.com/paper/2007.06225/) (2020)
- [Edge Directionality Improves Learning on Heterophilic Graphs](https://mlsanity.com/paper/2305.10498/) (2023)

## Abstract (arXiv)

Introduction Accurate prediction of protein-protein interactions (PPIs) is crucial for understanding cellular functions and advancing drug development. Existing in-silico methods use direct sequence embeddings from Protein Language Models (PLMs). Others use Graph Neural Networks (GNNs) for 3D protein structures. This study explores less computationally intensive alternatives. We introduce a novel framework for downstream PPI prediction through link prediction. Methods We introduce a two-stage graph representation learning framework, ProtGram-DirectGCN. First, we developed ProtGram. This approach models a protein's primary structure as a hierarchy of globally inferred n-gram graphs. In these graphs, residue transition probabilities define edge weights. Each edge connects a pair of residues in a directed graph. The probabilities are aggregated from a large corpus of sequences. Second, we propose DirectGCN, a custom directed graph convolutional neural network. This model features a unique convolutional layer. It processes information through separate path-specific transformations: incoming, outgoing, and undirected. A shared transformation is also applied. These paths are combined via a learnable gating mechanism. We apply DirectGCN to ProtGram graphs to learn residue-level embeddings. These embeddings are pooled via attention to generate protein-level embeddings for prediction. Results We first established the efficacy of DirectGCN on standard node classification benchmarks. Its performance matches established methods on general datasets. The model excels at complex, directed graphs with dense, heterophilic structures. When applied to PPI prediction, the full ProtGram-DirectGCN framework delivers robust predictive power. This strong performance holds even with limited training data.