IRIS Integrates Sparse Sequence, Experimental, and AI-Predicted Structures for Protein-RNA Affinity Prediction and Motif Discovery

Protein–RNA interactions are fundamental to numerous cellular processes, yet quantitatively characterizing their binding specificity remains a major challenge. We present IRIS (Integrative RNA–protein interaction prediction Informed by Structure and sequence), a biophysical framework that combines residue-level sequence and structural features to predict binding affinities and identify binding motifs. Applied across different protein-RNA systems, IRIS accurately predicts the effects of multiple RNA mutations, with performance further improved by incorporating additional high-affinity binders into training. By integrating predicted structural complexes, IRIS reveals alternative binding modes not observed in experimental structures, extends applicability to systems lacking experimental protein–RNA complexes, and generates a library of favorable RNA-binding motifs at protein–RNA interfaces. Collectively, these results establish IRIS as a versatile framework that leverages increasingly accurate structural predictions to enable quantitative modeling and rational engineering of protein-RNA interactions.