MM/GBSA and LIE estimates of host-guest affinities: dependence on charges and solvation model

The affinities of two sets of guest-host systems were estimated using the popular end-point methods MM/GBSA (molecular-mechanics with generalised Born and surface-area solvation) and LIE (linear interaction energy). A set of six primary alcohols that bind to α-cyclodextrin (α-CD) and a set of eight guest molecules to cucurbit[8]uril (CB8) were considered. Three different charge schemes were used to obtain charges for the host and guest molecules, viz., AM1-BCC, RESP, and the recently suggested xAvESP (which average ESP charges over a number of molecular dynamics snapshots). Furthermore, both the generalised Born and Poisson-Boltzmann solvation models were used in the MM/GBSA calculations. The two solvation models perform equally well in predicting relative affinities, and hence there is no point in using the more expensive Poisson-Boltzmann model for these systems. Both the LIE and MM/GBSA estimates are shown to be robust with respect to the charge model, and therefore it is recommended to use the cheapest AM1-BCC charges. Using AM1-BCC charges, the MM/GBSA method gave a MADtr (mean absolute deviation after removal of systematic error) of 17 kJ/mol and a correlation coefficient (r (2)) of 0.67 for the CB8 complexes, and a MADtr of 10 kJ/mol and an r (2) of 0.96 for the α-CD complexes. The LIE method gave a MADtr of 20 kJ/mol and an r (2) of 0.10 for the CB8 complexes, after optimisation of the non-polar scaling parameter. For the α-CD complexes, no optimisation was necessary and the method gave a MADtr of 2 kJ/mol and a r (2) of 0.96. These results indicate that both MM/GBSA and LIE are able to estimate host-guest affinities accurately.