HYDROPHOBE Challenge: A Joint Experimental and Computational Study on the Host–Guest Binding of Hydrocarbons to Cucurbiturils, Allowing Explicit Evaluation of Guest Hydration Free-Energy Contributions

Abstract

The host-guest complexation of hydrocarbons (22 guest molecules) with cucurbit[7]uril was investigated in aqueous solution using the indicator displacement strategy. The binding constants (10³-10⁹ M^-1) increased with guest size, pointing to the hydrophobic effect and dispersion interactions as driving forces. The measured affinities provide unique benchmark data for the binding of neutral guest molecules. Consequently, a computational blind challenge, the HYDROPHOBE challenge, was conducted to allow a comparison with state-of-the-art computational methods for predicting host-guest affinity constants. In total, three quantum-chemical (QM) data sets and two explicit-solvent molecular dynamics (MD) submissions were received. When searching for sources of uncertainty in predicting the host-guest affinities, the experimentally known hydration energies of the investigated hydrocarbons were used to test the employed solvation models (explicit solvent for MD and COSMO-RS for QM). Good correlations were obtained for both solvation models, but a rather constant offset was observed for the COSMO data, by ca. +2 kcal mol^-1, which was traced back to a required reference-state correction in the QM submissions (2.38 kcal mol^-1). Introduction of the reference-state correction improved the predictive power of the QM methods, particularly for small hydrocarbons up to C5.