Identification of RNA‐dependent liquid‐liquid phase separation proteins using an artificial intelligence strategy

Abstract RNA‐dependent liquid‐liquid phase separation (LLPS) proteins play critical roles in cellular processes such as stress granule formation, DNA repair, RNA metabolism, germ cell development, and protein translation regulation. The abnormal behavior of these proteins is associated with various diseases, particularly neurodegenerative disorders like amyotrophic lateral sclerosis and frontotemporal dementia, making their identification crucial. However, conventional biochemistry‐based methods for identifying these proteins are time‐consuming and costly. Addressing this challenge, our study developed a robust computational model for their identification. We constructed a comprehensive dataset containing 137 RNA‐dependent and 606 non‐RNA‐dependent LLPS protein sequences, which were then encoded using amino acid composition, composition of K‐spaced amino acid pairs, Geary autocorrelation, and conjoined triad methods. Through a combination of correlation analysis, mutual information scoring, and incremental feature selection, we identified an optimal feature subset. This subset was used to train a random forest model, which achieved an accuracy of 90% when tested against an independent dataset. This study demonstrates the potential of computational methods as efficient alternatives for the identification of RNA‐dependent LLPS proteins. To enhance the accessibility of the model, a user‐centric web server has been established and can be accessed via the link: http://rpp.lin‐group.cn .