Thermodynamic and kinetic specificities of ligand binding

Binding affinity and specificity are crucial for biomolecular recognition. Past studies have focused on binding affinity while the quantification of specificity has remained an elusive challenge. The conventional specificity measures the discrimination of the specific receptor against others for a ligand binding. It is difficult to explore all the possible competing receptors for the ligand. Here, we quantified the thermodynamic intrinsic specificity of discriminating the “native” binding mode against the “non-native” binding modes. Intrinsic specificity is relatively easy to compute since one doesn't need to explore all the other receptors. We found that the thermodynamic intrinsic specificity correlates with the conventional specificity. This validates the statistical equivalence of conventional and intrinsic specificities for receptors at reasonable size. We also computationally quantified the residence time of a ligand on the receptor target as the kinetic specificity. We found that the kinetic specificity correlates with the thermodynamic intrinsic specificity and the binding affinity, suggesting the kinetics and the thermodynamics can be simultaneously optimized for biological activities. With the thermodynamic and kinetic specificities in addition to affinity, we carried out a drug screening test on the target cyclooxygenase-2 (COX-2). We showed that multidimensional (two- and three-dimensional) screening has higher capability than affinity alone to discriminate the drug target (COX-2) from the competitive receptor (COX-1), and the selective drugs from the non-selective drugs. Our work suggests a new way of multidimensional drug screening and target identification, which has significant potential applications for drug discovery and design.

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