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Force-field and quantum-mechanical binding study of selected SAMPL3 host-guest complexes

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Abstract

A Merck molecular force field classical potential combined with Poisson-Boltzmann electrostatics (MMFF/PB) has been used to estimate the binding free energy of seven guest molecules (six tertiary amines and one primary amine) into a synthetic receptor (acyclic cucurbit[4]uril congener) and two benzimidazoles into cyclic cucurbit[7]uril (CB[7]) and cucurbit[8]uril (CB[8]) hosts. In addition, binding enthalpies for the benzimidazoles were calculated with density functional theory (DFT) using the B3LYP functional and a polarizable continuum model (PCM). Although in most cases the MMFF/PB approach returned reasonable agreements with the experiment (±2 kcal/mol), significant, much larger deviations were reported in the case of three host-guest pairs. All four binding enthalpy predictions with the DFT/PCM method suffered 70% or larger deviations from the calorimetry data. Results are discussed in terms of the molecular models used for guest-host complexation and the quality of the intermolecular potentials.

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Acknowledgments

We thank Anthony Nicholls, Geoff Skillman, Mike Word, Chris Bayly and Matt Geballe for the encouragement to participate in the SAMPL3 challenge and for numerous discussions and suggestions. In particular, we want to acknowledge Chris for his advice regarding the charge state of Host1 and Mike Word for detailed discussions about the importance of augmenting continuum solvent models with explicit solvent molecules.

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Correspondence to Stanislaw Wlodek.

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Hamaguchi, N., Fusti-Molnar, L. & Wlodek, S. Force-field and quantum-mechanical binding study of selected SAMPL3 host-guest complexes. J Comput Aided Mol Des 26, 577–582 (2012). https://doi.org/10.1007/s10822-012-9553-2

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  • DOI: https://doi.org/10.1007/s10822-012-9553-2

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