Evidence for ligandable sites in structured RNA throughout the Protein Data Bank

Abstract

RNA has attracted considerable attention as a target for small molecules. However, methods to identify, study, and characterize suitable RNA targets have lagged behind strategies for protein targets. One approach that has received considerable attention for protein targets has been to utilize computational analysis to investigate ligandable "pockets" on proteins that are amenable to small molecule binding. These studies have shown that selected physical properties of pockets are important parameters that govern the ability of a structure to bind to small molecules. This work describes a similar analysis to study pockets on all RNAs in the Protein Data Bank (PDB). Using parameters such as buriedness, hydrophobicity, volume, and other properties, the set of all RNAs is analyzed and compared to all proteins. Considerable overlap is observed between the properties of pockets on RNAs and proteins. Thus, many RNAs are capable of populating conformations with pockets that are likely suitable for small molecule binding. Further, principal moment of inertia (PMI) calculations reveal that liganded RNAs exist in diverse structural space, much of which overlaps with protein structural space. Taken together, these results suggest that complex folded RNAs adopt unique structures with pockets that may represent viable opportunities for small molecule targeting.

Keywords: Computational analysis; Ligandability; Nucleic acid structure; RNA; Small molecule.