GPTrans: A Biological Language Model-Based Approach for Predicting Disease-Associated Mutations in G Protein-Coupled Receptors.

Abstract

Accurately predicting mutations in G protein-coupled receptors (GPCRs) is critical for advancing disease diagnosis and drug discovery. In response to this imperative, GPTrans has emerged as a highly accurate predictor of disease-related mutations in GPCRs. The core innovation of GPTrans resides in the design of a novel feature extraction network, that is capable of integrating features from both wildtype and mutant protein variant sites, utilizing multifeature connections within a transformer framework to ensure comprehensive feature extraction. A key aspect of GPTrans's effectiveness is our introduction of an innovative deep feature integration strategy, which merges embeddings and class tokens from multiple protein language models, including evolutionary scale modeling and ProtTrans, thus shedding light on the biochemical properties of proteins. Leveraging transformer components and a self-attention mechanism, GPTrans captures higher-level representations of protein features. Employing both wildtype and mutation site information for feature fusion not only enriches the predictive feature set but also avoids the common issue of overestimation associated with sequence-based predictions. This approach distinguishes GPTrans, enabling it to significantly outperform existing methods. Our evaluations across diverse GPCR data sets, including ClinVar and MutHTP, demonstrate GPTrans's superior performance, with average AUC values of 0.874 and 0.590 in 10-fold cross-validation. Notably, compared to the AlphaMissense method, GPTrans exhibited a remarkable 38.03% improvement in accuracy when predicting disease-associated mutations in the MutHTP data set. A thorough analysis of the predicted results further validates the model's effectiveness. The source code, data sets, and prediction results for GPTrans are available for academic use at https://github.com/EduardWang/GPTrans.