Comparison of Entropic Contributions to Binding in a “Hydrophilic” versus “Hydrophobic” Ligand−Protein Interaction

Abstract

In the present study we characterize the thermodynamics of binding of histamine to recombinant histamine-binding protein (rRaHBP2), a member of the lipocalin family isolated from the brown-ear tick Rhipicephalus appendiculatus. The binding pocket of this protein contains a number of charged residues, consistent with histamine binding, and is thus a typical example of a “hydrophilic” binder. In contrast, a second member of the lipocalin family, the recombinant major urinary protein (rMUP), binds small hydrophobic ligands, with a similar overall entropy of binding in comparison with rRaHBP2. Having extensively studied ligand binding thermodynamics for rMUP previously, the data we obtained in the present study for HBP enables a comparison of the driving forces for binding between these classically distinct binding processes in terms of entropic contributions from ligand, protein, and solvent. In the case of rRaHBP2, we find favorable entropic contributions to binding from desolvation of the ligand; however, the overall entropy of binding is unfavorable due to a dominant unfavorable contribution arising from the loss of ligand degrees of freedom, together with the sequestration of solvent water molecules into the binding pocket in the complex. This contrasts with binding in rMUP where desolvation of the protein binding pocket makes a minor contribution to the overall entropy of binding given that the pocket is substantially desolvated prior to binding.

Will molecular dynamics simulations of proteins ever reach equilibrium?

“…from the solvent). 39 Such studies have been performed several times before 16,21,22,23,24,25,26,27,28,29 and we followed the protocol developed in those studies: We performed 500 ns simulations of two ligand-bound states of the Gal3 protein and 380 ns simulations of two ligand-bound states of MMP12. The protein conformational entropies were then estimated by the DDH approach.…”

“…16,17,19,20 Therefore, MD simulations are often used to supplement the NMR measurements to provide the total conformational entropy of the protein. 16,21,22,23,24,25,26,27,28,29 Protein conformational entropies are the main topic of this study, but it should be remembered that there are other important contributions to the total entropy as well, e.g. from the solvent.…”

Mechanism of the hydrophobic effect in the biomolecular recognition of arylsulfonamides by carbonic anhydrase

“…Experimentalists have rationalized enthalpically favorable association by invoking either (i) enthalpically favorable interactions between hosts and guests in the bound complex (so-called "nonclassical" hydrophobic effects) (4,32,33), or (ii) the "release" of water molecules upon association that, because of the structure of the binding pocket, adopt configurations that are enthalpically less favorable than bulk water (25,34,35). Many of these experimental studies, which have relied heavily on modern isothermal titration calorimeters (ITC), have also shown negative values of the heat capacity of association (ΔC p ∘ ) (26,27,(36)(37)(38)(39)(40), a term that has since become the sign-post of hydrophobic interactions-even though changes in heat capacity result, in principle, from myriad structural changes that occur with association in aqueous solution (41)(42)(43).…”

Interaction of clozapine and its nitrenium ion with rat D2 dopamine receptors: in vitro binding and computational study

“…Nevertheless, the lack of binding affinity of the nitrenium ion might be also explained by a desolvation penalty higher than that of clozapine due to the presence of a double positive charge. Indeed, contribution of desolvation to binding affinity was proposed in some protein-ligand complexes [34][35][36][37].…”