Iterative Evolution of an Abiotic Foldamer Sequence for the Recognition of Guest Molecules with Atomic Precision

A synthetic helical
aromatic oligoamide foldamer receptor with
high affinity and selectivity for tartaric acid was subjected to a
structure-based evolution of its sequence via mutations, additions,
and deletions of monomers to produce a new receptor having high affinity
and selectivity for malic acid, a guest that differs from tartaric
acid by a single oxygen atom. Seven iteratively modified sequences
were synthesized. Detailed structural investigations of host–guest
complexes were carried out systematically to guide the design of the
next generation. A first outcome was a reversal of selectivity of
the receptors, with a starting preference for tartaric acid over malic
acid of over 102 and an ending sequence showing a preference
for malic acid over tartaric acid of over 102. Another
outcome was a very strong enhancement of the affinity for malic acid,
despite the fact that it has fewer recognition features for binding
through polar interactions such as hydrogen bonds. Such a level of
discrimination between resembling guests exemplifies the amenability
of foldamers to outstanding achievements in molecular recognition.
Altogether, our results demonstrate the viability of a rational receptor
design approach that exploits the modularity of foldamer sequences
and, in the case of aromatic amide foldamers, their amenability to
structural elucidation, their relative ease of synthesis, and the
predictability of their structure.