An Investigation into the Structural Basis for Nucleic Acid Small Molecule Binding

The past 30 years of RNA research have seen a fundamental shift in our understanding of the biological roles that these macromolecules play. The sea change from our initial conception of RNA as a mere messenger of genetic information between DNA and proteins to our current understanding of RNA as a key player in various genetic and metabolic roles through their non-coding counterparts has motivated attempts to elucidate the structural underpinnings of their various biological functions. In this thesis, I describe research to develop and implement methods that formally represent nucleic acid structure, query and reason over their properties and computationally identify RNA structural motifs that are predictive of ligand binding. Chapter 1 presents the motivation, overall hypothesis and main objectives for this doctoral research, as well as a brief overview of the principles of nucleic acid structure and their representation using Semantic Web technologies. In Chapter 2, I present the RNA Knowledge Base (RKB), an instantiated ontology about RNA structure that provides machine understandable descriptions of nucleotide base pairs as observed in solved 3D structures. In Chapter 3, I describe Aptamer Base, a collaborative online knowledge base to describe aptamers and the details of the SELEX experiments that created them. In Chapter 4, I describe a methodology and implementation for the computational extraction of RNA motifs from a graph representation of their structures, and demonstrate that features of these motifs are predictive of ligand binding. In Chapter 5, I discuss future directions and present a summary of the contributions of this thesis.