Spatial mismatch, non-additive binding energies and selectivity in supramolecular complexes

The consequences of spatial mismatch between a receptor and ligand on affinity and selectivity of supramolecular complexes are illustrated with several examples. Conformationally rigid complexes and shorter-range non-covalent forces are characterized by large affinity changes, in contrast to more flexible systems. In the most frequent complexes with several spaciously separated binding sites, the additivity of binding energies and the correlation between affinity and selectivity is often lost by partial mismatch. Complete changes of binding modes and preferences can be the consequence, as illustrated particularly with cyclodextrin complexes. Associations with biopolymers, which usually depend also on several interaction sites, rarely show affinity-selectivity correlations, particularly not for high-affinity drug-receptor interactions. The negative consequences of spatial mismatch can be reduced by the introduction of flexible linkers between one binding site which secures affinity and the other one responsible for selectivity.