Entropy in molecular recognition by proteins

Molecular recognition by proteins is fundamental to molecular biology. Dissection of the thermodynamic energy terms governing protein–ligand interactions has proven difficult, with determination of entropic contributions being particularly elusive. NMR relaxation measurements have suggested that changes in protein conformational entropy can be quantitatively obtained through a dynamical proxy, but the generality of this relationship has not been shown. Twenty-eight protein–ligand complexes are used to show a quantitative relationship between measures of fast side-chain motion and the underlying conformational entropy. We find that the contribution of conformational entropy can range from favorable to unfavorable, which demonstrates the potential of this thermodynamic variable to modulate protein–ligand interactions. For about one-quarter of these complexes, the absence of conformational entropy would render the resulting affinity biologically meaningless. The dynamical proxy for conformational entropy or “entropy meter” also allows for refinement of the contributions of solvent entropy and the loss in rotational-translational entropy accompanying formation of high-affinity complexes. Furthermore, structure-based application of the approach can also provide insight into long-lived specific water–protein interactions that escape the generic treatments of solvent entropy based simply on changes in accessible surface area. These results provide a comprehensive and unified view of the general role of entropy in high-affinity molecular recognition by proteins.

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Measuring Entropy in Molecular Recognition by Proteins

Annual Review of Biophysics ◽

10.1146/annurev-biophys-060414-034042 ◽

2018 ◽

Vol 47 (1) ◽

pp. 41-61 ◽

Cited By ~ 34

Author(s):

A. Joshua Wand ◽

Kim A. Sharp

Keyword(s):

Molecular Recognition ◽

Protein Function ◽

Conformational Entropy ◽

Protein Ligand Interactions ◽

Relaxation Measurements ◽

Ligand Interactions ◽

Resonance Relaxation ◽

Translational Entropy ◽

Side Chain Motion

Molecular recognition by proteins is fundamental to the molecular basis of biology. Dissection of the thermodynamic landscape governing protein–ligand interactions has proven difficult because determination of various entropic contributions is quite challenging. Nuclear magnetic resonance relaxation measurements, theory, and simulations suggest that conformational entropy can be accessed through a dynamical proxy. Here, we review the relationship between measures of fast side-chain motion and the underlying conformational entropy. The dynamical proxy reveals that the contribution of conformational entropy can range from highly favorable to highly unfavorable and demonstrates the potential of this key thermodynamic variable to modulate protein–ligand interactions. The dynamical so-called entropy meter also refines the role of solvent entropy and directly determines the loss in rotational–translational entropy that occurs upon formation of high-affinity complexes. The ability to quantify the roles of entropy through an entropy meter based on measurable dynamical properties promises to highlight its role in protein function.

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Conformational dynamics and thermodynamics of protein–ligand binding studied by NMR relaxation

Biochemical Society Transactions ◽

10.1042/bst20110750 ◽

2012 ◽

Vol 40 (2) ◽

pp. 419-423 ◽

Cited By ~ 46

Author(s):

Mikael Akke

Keyword(s):

Ligand Binding ◽

Bound States ◽

Conformational Dynamics ◽

Nmr Relaxation ◽

Titration Calorimetry ◽

Conformational Entropy ◽

Chain Order ◽

Ligand Interactions ◽

Galectin 3 ◽

Relaxation Experiments

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 the present paper, I focus on the second topic, summarizing our recent results on the role of conformational entropy in ligand binding to Gal3C (the carbohydrate-recognition domain of galectin-3). NMR relaxation experiments provide a unique probe of 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.

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