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

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.