Chemical modifications have a peculiar place in aptamer development. They often come into play only after something has already gone wrong: an aptamer is degraded too quickly in serum, cleared from the bloodstream too rapidly, or loses activity at 37 °C. The usual response is to introduce 2′-OMe residues, protect one end, attach PEG and measure the properties again.

That approach makes sense, but a chemical modification rarely affects only the parameter it was meant to improve. Replacing a single atom or a small functional group can substantially change how long a molecule survives. Modified bases can form contacts with proteins that natural DNA or RNA cannot, while a change introduced to improve stability can alter the geometry of the binding site and, with it, affinity. At the atomic level, every substitution creates a different molecule, with different energetics, dynamics and sometimes a different mode of interaction with its target.