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

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Abstract

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.

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Acknowledgments

This investigation has been supported by grants from the Research school in pharmaceutical science. It has also been supported by computer resources of LUNARC at Lund University (project SNIC001-10-225), NSC at Linköping University and HPC2 N at Umeå University (project SNIC014-10-24). Prof. Ulf Ryde and Svante Hedström are acknowledged for discussions and critical proofreading.

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  1. Division of Theoretical Chemistry, Department of Chemistry, Lund University, P. O. Box 124, 221 00, Lund, Sweden

    Samuel Genheden

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  1. Samuel Genheden
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Correspondence to Samuel Genheden.

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Genheden, S. MM/GBSA and LIE estimates of host–guest affinities: dependence on charges and solvation model. J Comput Aided Mol Des 25, 1085–1093 (2011). https://doi.org/10.1007/s10822-011-9486-1

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