The power and limits of predicting exon-exon interactions using protein 3D structures

Alternative splicing (AS) effects on cellular functions can be captured by studying changes in the underlying protein-protein interactions (PPIs). Because AS results in the gain or loss of exons, existing methods for predicting AS-related PPI changes utilize known PPI interfacing exon-exon interactions (EEIs), which only cover [~]5% of known human PPIs. Hence, there is a need to extend the existing limited EEI knowledge to advance the functional understanding of AS. In this study, we explore whether existing computational PPI interface prediction (PPIIP) methods, originally designed to predict residue-residue interactions (RRIs), can be used to predict EEIs. We evaluate three recent state-of-the-art PPIIP methods for the RRI- as well as EEI-prediction tasks using known protein complex structures, covering [~]230,000 RRIs and [~]27,000 EEIs. Our results provide the first evidence that existing PPIIP methods can be extended for the EEI prediction task, showing F-score, precision, and recall performances of up to [~]38%, [~]63%, and [~]28%, respectively, with a false discovery rate of less than 5%. Our study provides insights into the power and limits of existing PPIIP methods to predict EEIs, thus guiding future developments of computational methods for the EEI prediction task. We provide streamlined computational pipelines integrating each of the three considered PPIIP methods for the EEI prediction task to be utilized by the scientific community.