University of Cambridge > > Biophysical Seminars > Dynamics and thermodynamics of ligand binding to galectin-3

Dynamics and thermodynamics of ligand binding to galectin-3

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Protein conformational dynamics can be critical for ligand binding in two ways that relate to kinetics and thermodynamics respectively. First, conformational transitions between different substates can control access to the binding site (kinetics). Secondly, differences between free and ligand-bound states in their conformational fluctuations contribute to the entropy of ligand binding (thermodynamics). In my talk I will summarize our results on the role of conformational dynamics in ligand binding to the carbohydrate-recognition domain of galectin-3. NMR relaxation experiments uniquely probe conformational entropy by characterizing bond-vector fluctuations at atomic resolution. By monitoring differences between the free and ligand-bound states in their backbone and side chain order parameters, we have estimated the contributions from conformational entropy to the free energy of binding. Overall, the conformational entropy of Gal3C increases upon ligand binding, thereby contributing favourably to the binding affinity. Comparisons with the results from isothermal titration calorimetry indicate that the conformational entropy is comparable in magnitude to the enthalpy of binding. Furthermore, there are significant differences in the dynamic response to binding of different ligands, despite the fact that the protein structure is virtually identical in the different protein–ligand complexes. Thus both affinity and specificity of ligand binding to Gal3C appear to depend in part on subtle differences in the conformational fluctuations that reflect the complex interplay between structure, dynamics and ligand interactions. We have also studied the kinetics of ligand binding using CPMG relaxation dispersion experiments. By monitoring the on- and off-rates of binding for a series of related compounds, we resolve linear free energy relationships that reveal the relative stabilization of the bound state and transition state, as well as the position of the transition state along the reaction coordinate. Experiments conducted with variable ligand concentration provide information on the relative importance of (or relative flux through) the so-called induced fit and conformational selection pathways of ligand binding.

This talk is part of the Biophysical Seminars series.

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