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Abstract
Understanding the driving forces underlying molecular recognition is of fundamental importance in chemistry and biology. The challenge is to unravel the binding thermodynamics into separate contributions and to interpret these in molecular terms. Entropic contributions to the free energy of binding are particularly difficult to assess in this regard. Here we pinpoint the molecular determinants underlying differences in ligand affinity to the carbohydrate recognition domain of galectin-3, using a combination of isothermal titration calorimetry, X-ray crystallography, NMR relaxation, and molecular dynamics simulations followed by conformational entropy and grid inhomogeneous solvation theory (GIST) analyses. Using a pair of diastereomeric ligands that have essentially identical chemical potential in the unbound state, we reduced the problem of dissecting the thermodynamics to a comparison of the two protein-ligand complexes. While the free energies of binding are nearly equal for the R and S diastereomers, greater differences are observed for the enthalpy and entropy, which consequently exhibit compensatory behavior, ΔΔ H°(R - S) = -5 ± 1 kJ/mol and - TΔΔ S°(R - S) = 3 ± 1 kJ/mol. NMR relaxation experiments and molecular dynamics simulations indicate that the protein in complex with the S-stereoisomer has greater conformational entropy than in the R-complex. GIST calculations reveal additional, but smaller, contributions from solvation entropy, again in favor of the S-complex. Thus, conformational entropy apparently dominates over solvation entropy in dictating the difference in the overall entropy of binding. This case highlights an interplay between conformational entropy and solvation entropy, pointing to both opportunities and challenges in drug design.
Highlights
Molecular recognition is fundamental to biology in that it governs signaling within and between cells, with prominent examples provided by the immune system, hormonal control of distant organs in higher organisms, and specificity of enzyme reactions
We investigated the driving forces underlying affinity and selectivity in ligand binding by carrying out a comparative analysis involving the binding of two diastereomeric ligands R and S (Figure 1) to galectin-3C
Article thioxanthate) and glycidyl electrophiles gave lower yields and stereochemical scrambling due to nucleophilic attack occurring on both C1 and C3 of the glycidyl derivatives, or due to epoxide opening followed by intramolecular substitution to epoxide reclosing
Summary
Molecular recognition is fundamental to biology in that it governs signaling within and between cells, with prominent examples provided by the immune system, hormonal control of distant organs in higher organisms, and specificity of enzyme reactions. Modern medicine is to a large extent based on the possibility to interfere with and control molecular recognition by the design of synthetic ligands or effectors that bind to a specific protein in a given signaling pathway. Drug design aims to generate such protein ligands that have high affinity and specificity for the target. One reason is that the free energy of binding is in most cases a small difference between large numbers arising from the different interactions between the protein, ligand, other solutes, and solvent molecules. Entropic contributions can be significant because proteins have many degrees of freedom, are generally flexible, and populate a wide range of conformations. Recent work has highlighted the role of protein conformational entropy in ligand binding,[1−8] as well as the highly heterogeneous response of water molecules around binding sites[9−12] and ligands.[13]
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