PNAbind: Structure-based prediction of protein-nucleic acid binding using graph neural networks.

ABSTRACT

The recognition and binding of nucleic acids (NAs) by proteins depends upon complementary chemical, electrostatic and geometric properties of the protein-NA binding interface. Structural models of protein-NA complexes provide insights into these properties but are scarce relative to models of unbound proteins. We present a deep learning approach for predicting protein-NA binding given the apo structure of a protein (PNAbind). Our method utilizes graph neural networks to encode spatial distributions of physicochemical and geometric properties of the protein molecular surface that are predictive of NA binding. Using global physicochemical encodings, our models predict the overall binding function of a protein and can discriminate between specificity for DNA or RNA binding. We show that such predictions made on protein structures modeled with AlphaFold2 can be used to gain mechanistic understanding of chemical and structural features that determine NA recognition. Using local encodings, our models predict the location of NA binding sites at the level of individual binding residues. Binding site predictions were validated against benchmark datasets, achieving AUROC scores in the range of 0.92-0.95. We applied our models to the HIV-1 restriction factor APOBEC3G and show that our predictions are consistent with experimental RNA binding data.