Allosteric Mechanisms of Nonadditive Substituent Contributions to Protein-Ligand Binding.

ABSTRACT: Quantifying chemical substituent contributions to ligand-binding free energies is challenging due to nonadditive effects. Protein allostery is a frequent cause of nonadditivity, but the underlying allosteric mechanisms often remain elusive. Here, we propose a general NMR-based approach to elucidate such mechanisms and we apply it to the HCN4 ion channel, whose cAMP-binding domain is an archetypal conformational switch. Using NMR, we show that nonadditivity arises not only from concerted conformational transitions, but also from conformer-specific effects, such as steric frustration. Our results explain how affinity-reducing functional groups may lead to affinity gains if combined. Surprisingly, our approach also reveals that nonadditivity depends markedly on the receptor conformation. It i

SUBMITTER: Boulton S 

PROVIDER: S-EPMC7499118 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature