A Nexus between Theory and Experiment: Non-Empirical Quantum Mechanical Computational Methodology Applied to Cucurbit[n]uril⋅Guest Binding Interactions.

A training set of eleven X-ray structures determined for biomimetic complexes between cucurbit[n]uril (CB[7 or 8]) hosts and adamantane-/diamantane ammonium/aminium guests were studied with DFT-D3 quantum mechanical computational methods to afford G(calcd) binding energies. A novel feature of this work is that the fidelity of the BLYP-D3/def2-TZVPP choice of DFT functional was proven by comparison with more accurate methods. For the first time, the CB[n]guest complex binding energy subcomponents [for example, E-dispersion, E-electrostatic, G(solvation), binding entropy (-TS), and induced fit E-deformation(host), E-deformation(guest)] were calculated. Only a few weeks of computation time per complex were required by using this protocol. The deformation (stiffness) and solvation properties (with emphasis on cavity desolvation) of cucurbit[n]uril (n=5, 6, 7, 8) isolated host molecules were also explored by means of the DFT-D3 method. A high (2)=0.84 correlation coefficient between G(exptl) and G(calcd) was achieved without any scaling of the calculated terms (at 298K). This linear dependence was utilized for G(calcd) predictions of new complexes. The nature of binding, including the role of high energy water molecules, was also studied. The utility of introduction of tethered [-(CH2)(n)NH3](+) amino loops attached to N,N-dimethyl-adamantane-1-amine and N,N,N,N-tetramethyl diamantane-4,9-diamine skeletons (both from an experimental and a theoretical perspective) is presented here as a promising tool for the achievement of new ultra-high binding guests to CB[7] hosts. Predictions of not yet measured equilibrium constants are presented herein.