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Free-energy perturbation and quantum mechanical study of SAMPL4 octa-acid host–guest binding energies

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Abstract

We have estimated free energies for the binding of nine cyclic carboxylate guest molecules to the octa-acid host in the SAMPL4 blind-test challenge with four different approaches. First, we used standard free-energy perturbation calculations of relative binding affinities, performed at the molecular-mechanics (MM) level with TIP3P waters, the GAFF force field, and two different sets of charges for the host and the guest, obtained either with the restrained electrostatic potential or AM1-BCC methods. Both charge sets give good and nearly identical results, with a mean absolute deviation (MAD) of 4 kJ/mol and a correlation coefficient (R 2) of 0.8 compared to experimental results. Second, we tried to improve these predictions with 28,800 density-functional theory (DFT) calculations for selected snapshots and the non-Boltzmann Bennett acceptance-ratio method, but this led to much worse results, probably because of a too large difference between the MM and DFT potential-energy functions. Third, we tried to calculate absolute affinities using minimised DFT structures. This gave intermediate-quality results with MADs of 5–9 kJ/mol and R 2 = 0.6–0.8, depending on how the structures were obtained. Finally, we tried to improve these results using local coupled-cluster calculations with single and double excitations, and non-iterative perturbative treatment of triple excitations (LCCSD(T0)), employing the polarisable multipole interactions with supermolecular pairs approach. Unfortunately, this only degraded the predictions, probably because of a mismatch between the solvation energies obtained at the DFT and LCCSD(T0) levels.

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Acknowledgments

This investigation has been supported by Grants from the Swedish research council (project 2010-5025). The computations were performed on computer resources provided by the Swedish National Infrastructure for Computing (SNIC) at Lunarc at Lund University and HPC2N at Umeå University. The collaboration between the Universities of Lund and Göttingen has been carried out within the framework of the International Research Training Group 1422 Metal Sites in Biomolecules—Structures, Regulation, Mechanisms and M. A. is supported through a Ph.D. scholarship in this International Research Training Group. D. C. thanks FEBS for a short-term fellowship. We are grateful to Prof. Stefan Grimme for providing us with the thermo program.

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Authors and Affiliations

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

    Paulius Mikulskis, Daniela Cioloboc, Sakshi Khare, Joakim Brorsson, Pär Söderhjelm & Ulf Ryde

  2. Institut für Physikalische Chemie, Universität Göttingen, Tammannstrasse 6, 37077, Göttingen, Germany

    Milica Andrejić & Ricardo A. Mata

  3. School of Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, UK

    Samuel Genheden

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  1. Paulius Mikulskis
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Correspondence to Pär Söderhjelm or Ulf Ryde.

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Mikulskis, P., Cioloboc, D., Andrejić, M. et al. Free-energy perturbation and quantum mechanical study of SAMPL4 octa-acid host–guest binding energies. J Comput Aided Mol Des 28, 375–400 (2014). https://doi.org/10.1007/s10822-014-9739-x

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