<i>De novo</i> design of drug-binding proteins with predictable binding energy and specificity.

ABSTRACT: The de novo design of small-molecule-binding proteins has seen exciting recent progress; however, the ability to achieve exquisite affinity for binding small molecules while tuning specificity has not yet been demonstrated directly from computation. Here, we develop a computational procedure that results in the highest affinity binders to date with predetermined relative affinities, targeting a series of PARP1 inhibitors. Two of four designed proteins bound with affinities ranging from < 5 nM to low μM, in a predictable manner. X-ray crystal structures confirmed the accuracy of the designed protein-drug interactions. Molecular dynamics simulations informed the role of water in binding. Binding free-energy calculations performed directly on the designed models are in excellent agreement wit

SUBMITTER: Lu L 

PROVIDER: S-EPMC10769398 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature