Water-mediated ribonucleotide-amino acid pairs and higher-order structures at the RNA-protein interface: analysis of the crystal structure database and a topological classification.

Water is essential for the formation, stability and function of RNA-protein complexes. To delineate the structural role of water molecules in shaping the interactions between RNA and proteins, we comprehensively analyzed a dataset of 329 crystal structures of these complexes to identify water-mediated hydrogen-bonded contacts at RNA-protein interface. Our survey identified a total of 4963 water bridges. We then employed a graph theory-based approach to present a robust classification scheme, encompassing triplets, quartets and quintet bridging topologies, each further delineated into sub-topologies. The frequency of water bridges within each topology decreases with the increasing degree of water node, with simple triplet water bridges outnumbering the higher-order topologies. Overall, this analysis demonstrates the variety of water-mediated interactions and highlights the importance of water as not only the medium but also the organizing principle underlying biomolecular interactions. Further, our study emphasizes the functional significance of water-mediated interactions in RNA-protein complexes, and paving the way for exploring how these interactions operate in complex biological environments. Altogether, this understanding not only enhances insights into biomolecular dynamics but also informs the rational design of RNA-protein complexes, providing a framework for potential applications in biotechnology and therapeutics. All the scripts, and data are available at https://github.com/PSCPU/waterbridges.