An interpretable deep geometric learning model to predict the effects of mutations on protein–protein interactions using large-scale protein language model

Protein–protein interactions (PPIs) are central to the mechanisms of signaling pathways and immune responses, which can help us understand disease etiology. Therefore, there is a significant need for efficient and rapid automated approaches to predict changes in PPIs. In recent years, there has been a significant increase in applying deep learning techniques to predict changes in binding affinity between the original protein complex and its mutant variants. Particularly, the adoption of graph neural networks (GNNs) has gained prominence for their ability to learn representations of protein–protein complexes. However, the conventional GNNs have mainly concentrated on capturing local features, often disregarding the interactions among distant elements that hold potential important information. In this study, we have developed a transformer-based graph neural network to extract features of the mutant segment from the three-dimensional structure of protein–protein complexes. By embracing both local and global features, the approach ensures a more comprehensive understanding of the intricate relationships, thus promising more accurate predictions of binding affinity changes. To enhance the representation capability of protein features, we incorporate a large-scale pre-trained protein language model into our approach and employ the global protein feature it provides. The proposed model is shown to be able to predict the mutation changes in binding affinity with a root mean square error of 1.10 and a Pearson correlation coefficient of near 0.71, as demonstrated by performance on test and validation cases. Our experiments on all five datasets, including both single mutant and multiple mutant cases, demonstrate that our model outperforms four state-of-the-art baseline methods, and the efficacy was subjected to comprehensive experimental evaluation. Our study introduces a transformer-based graph neural network approach to accurately predict changes in protein–protein interactions (PPIs). By integrating local and global features and leveraging pretrained protein language models, our model outperforms state-of-the-art methods across diverse datasets. The results of this study can provide new views for studying immune responses and disease etiology related to protein mutations. Furthermore, this approach may contribute to other biological or biochemical studies related to PPIs.

Scientific contribution Our scientific contribution lies in the development of a novel transformer-based graph neural network tailored to predict changes in protein–protein interactions (PPIs) with excellent accuracy. By seamlessly integrating both local and global features extracted from the three-dimensional structure of protein–protein complexes, and leveraging the rich representations provided by pretrained protein language models, our approach surpasses existing methods across diverse datasets. Our findings may offer novel insights for the understanding of complex disease etiology associated with protein mutations. The novel tool can be applicable to various biological and biochemical investigations involving protein mutations.