AI Insight
A large-scale analysis of 4,311 protein-small-molecule pairs reveals that binding kinetics, including both association and dissociation rates, are governed primarily by the intrinsic conformational dynamics of the protein rather than by the structural properties of the ligand. Counterintuitively, the rate at which a ligand dissociates shows little dependence on its molecular structure, suggesting that dissociation is controlled by protein-gated conformational transitions rather than by the direct breaking of protein-ligand contacts. This mechanism contrasts notably with protein-protein interactions, analyzed across 1,561 pairs, where different determinants appear to govern binding kinetics.
Why it matters
These findings challenge fundamental assumptions in drug design, particularly the strategy of optimizing ligand structure to control how long a drug remains bound to its target, known as residence time. If protein dynamics are the primary driver of binding kinetics, future drug development may need to focus more on selecting or engineering target proteins with favorable dynamic properties rather than solely refining ligand chemistry.
⚠️ Preprint – Noch nicht peer-reviewed
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Protein-ligand interactions underpin biological regulation and drug action, with both binding affinity and binding kinetics shaping functional outcomes. By analysing kinetic data for 4,311 protein-small-molecule pairs, we find that when association occurs below the diffusion controlled limit, the rates of ligand association (kon) and dissociation (koff ) are primarily determined by how the initial encounter complex reorganizes into the final bound state, and that this reorganization is governed chiefly by the intrinsic dynamic properties of the protein rather than by structural features of the ligand. Counterintuitively, therefore, koff exhibits minimal dependence on ligand structure, so that dissociation proceeds through protein gated conformational transitions rather than through direct rupture of protein-ligand contacts. This mechanistic behaviour stands in marked contrast to that for protein-protein complexes, based on an analysis of 1,561 interactions. Together, these findings challenge prevailing assumptions regarding the molecular determinants of small-molecule binding kinetics, and have broad implications for rationally modulating protein-ligand interactions and drug target residence times.
Source: Protein-ligand binding kinetics are primarily controlled by the protein, not the ligand.