Kinetic binding rate constants, together with equilibrium constants, provide a complete view of molecular recognition. In addition, modeling ligand-receptor binding/unbinding pathways can provide insights into molecular association, including intermolecular interactions, changes of solvent and solute entropy, barriers to binding, and conformational changes in the intermediate states. This presentation discusses the binding thermodynamics and kinetics for both solute and solvent. We will show the binding free energy landscape constructed by a Binding Kinetics Toolkit (BKiT) newly developed by our group. We applied molecular dynamics (MD) simulations for multiple guests binding to beta-cyclodextrin to compute binding enthalpy, entropy, and rate constants. The free energy profile using both umbrella sampling methods and milestoning theory with BKiT will be discussed. The investigation into multiple binding/unbinding pathways and the ensembles which represent the experimental data will be discussed as well. A kinase-ligand binding system and the applications to drug development will also be discussed.

Modeling ligand-receptor binding thermodynamics and kinetics: A comprehensive picture of molecular recognition

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ACS Spring 2023

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