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Conformational entropy in ligand binding and drug design

The role of conformational entropy in ligand binding

We would like to understand the ‘driving forces’ of protein–ligand binding, which amounts to understanding the statistical thermodynamics of the binding process at atomic resolution. In the ideal scenario, we would be able to attribute the contributions from individual molecular groups to the enthalpy and entropy of binding. Arguably, one of the greatest challenges lies in evaluating the conformational entropy of the target protein, which involves a very large number of degrees of freedom. This is perhaps one reason why protein conformational entropy has not received widespread attention in the field of ligand/drug design, while the often dominant role of solvent entropy is generally taken into account, together with the change in ligand entropy. For these reasons, we are interested in the role of the conformational entropy of the target protein in ligand-binding processes.

NMR relaxation experiments provide a unique probe of conformational entropy by characterizing bond-vector fluctuations at atomic resolution. By comparing NMR-derived order parameters between the free and ligand-bound protein, we estimate the contributions from conformational entropy to the free energy of ligand binding. We combine NMR relaxation experiments with molecular dynamics (MD) simulations to derive a highly detailed picture of how the conformational entropy changes when the protein binds different ligands. In collaboration with experts in computational chemistry, we aim to derive robust protocols for evaluating changes in conformational entropy that have been validated against NMR data. 

In addition to NMR relaxation methods, we use isothermal titration calorimetry to obtain the thermodynamic fingerprint of ligand binding, including the total (standard) free energy, enthalpy, and entropy of the process. 

As part of this project, we develop novel spin relaxation methods to improve the characterization of side-chain fluctuations. Our recent efforts have focused on aromatic side chains, which often are found in binding sites.