The temperature-dependence of host–guest binding thermodynamics: experimental and simulation studies

The thermodynamic parameters of host–guest binding can be used to describe, understand, and predict molecular recognition events in aqueous systems. However, interpreting binding thermodynamics remains challenging, even for these relatively simple molecules, as they are determined by both direct and solvent-mediated host–guest interactions. In this contribution, we focus on the contributions of water to binding by studying binding thermodynamics, both experimentally and computationally, for a series of nearly rigid, electrically neutral host–guest systems and report the temperature-dependent thermodynamic binding contributions ΔG(b)(T), ΔH(b)(T), ΔS(b)(T), and ΔC(p,b). Combining isothermal titration calorimetry (ITC) measurements with molecular dynamics (MD) simulations, we provide insight into the binding forces at play for the macrocyclic hosts cucurbit[n]uril (CBn, n = 7–8) and β-cyclodextrin (β-CD) with a range of guest molecules. We find consistently negative changes in heat capacity on binding (ΔC(p,b)) for all systems studied herein – as well as for literature host–guest systems – indicating increased enthalpic driving forces for binding at higher temperatures. We ascribe these trends to solvation effects, as the solvent properties of water deteriorate as temperature rises. Unlike the entropic and enthalpic contributions to binding, with their differing signs and magnitudes for the classical and non-classical hydrophobic effect, heat capacity changes appear to be a unifying and more general feature of host–guest complex formation in water. This work has implications for understanding protein–ligand interactions and other complex systems in aqueous environments.