Slow Molecular Recognition by RNA

Molecular recognition is fundamental to life as demonstrated by the remarkable specificity observed in biological processes mediated by proteins and RNAs. Nevertheless, the most accurate process is of no value to biology if it cannot be carried out rapidly. Proteins associate with ligands with a wide range of association rate constants, with maximal values matching the theoretical limit set by the rate of diffusional collision. As less is known about RNA association, we recently compiled association rate constants for all RNA/ligand complexes that we could find in the literature. Our analysis indicates that RNAs, like proteins, exhibit a wide range of association rate constants. However, the fastest RNA association rates are considerably slower than those of the fastest protein associations and fall well below the diffusional limit. The apparently general observation of slow association with RNAs presumably reflects basic physical properties of RNA and has implications for evolution and for modern‐day biology. We also discuss potential strategies for increasing RNA association kinetics, such as the use of electrostatic forces to accelerate binding, which may provide broadly applicable strategies for developing fast‐binding RNA ligands as well as RNA‐targeted therapeutics.