Fuzzy Interactions Open Perspectives toward Drugging Conformational Heterogeneity

Fuzzy interactions enable specific biomolecular recognition while maintaining conformational freedom of the interacting partners. Here, we propose that fuzziness can be exploited for allosteric regulation to provide context-specific functional outputs. Using receptor signaling as an illustrative example, we demonstrate how heterogeneous binding modes with ligands can be fine-tuned through transient interactions. Fuzzy interactions interfere with alternative positions or modulate the mobility to mimic the landscapes of specific functional states that are linked with certain environmental conditions. Furthermore, using allosteric drugs targeting the ABL1 tyrosine kinase, KRAS oncogene, and IDH2 enzyme as examples, we demonstrate how fuzzy interaction mechanisms can affect allosteric couplings in a functionally meaningful manner through rewiring heterogeneous contact patterns. These notions could be helpful for drug development, targeting dynamic conformational ensembles and biasing them toward context-specific functional states.