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Journal of Computer-Aided Molecular Design

, Volume 24, Issue 4, pp 343–353 | Cite as

Prediction of tautomer ratios by embedded-cluster integral equation theory

  • Stefan M. KastEmail author
  • Jochen Heil
  • Stefan Güssregen
  • K. Friedemann Schmidt
Article

Abstract

The “embedded cluster reference interaction site model” (EC-RISM) approach combines statistical-mechanical integral equation theory and quantum-chemical calculations for predicting thermodynamic data for chemical reactions in solution. The electronic structure of the solute is determined self-consistently with the structure of the solvent that is described by 3D RISM integral equation theory. The continuous solvent-site distribution is mapped onto a set of discrete background charges (“embedded cluster”) that represent an additional contribution to the molecular Hamiltonian. The EC-RISM analysis of the SAMPL2 challenge set of tautomers proceeds in three stages. Firstly, the group of compounds for which quantitative experimental free energy data was provided was taken to determine appropriate levels of quantum-chemical theory for geometry optimization and free energy prediction. Secondly, the resulting workflow was applied to the full set, allowing for chemical interpretations of the results. Thirdly, disclosure of experimental data for parts of the compounds facilitated a detailed analysis of methodical issues and suggestions for future improvements of the model. Without specifically adjusting parameters, the EC-RISM model yields the smallest value of the root mean square error for the first set (0.6 kcal mol−1) as well as for the full set of quantitative reaction data (2.0 kcal mol−1) among the SAMPL2 participants.

Keywords

Solvation model Quantum chemistry 3D RISM theory Cluster embedding Tautomer ratio 

Notes

Acknowledgments

We thank the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie, and the Adolf-Messer-Stiftung for financial support.

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Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Stefan M. Kast
    • 1
    • 2
    Email author
  • Jochen Heil
    • 1
    • 2
  • Stefan Güssregen
    • 3
  • K. Friedemann Schmidt
    • 3
  1. 1.Theoretische Physikalische ChemieTechnische Universität DortmundDortmundGermany
  2. 2.Eduard-Zintl-Institut für Anorganische und Physikalische ChemieTechnische Universität DarmstadtDarmstadtGermany
  3. 3.Sanofi-Aventis Deutschland GmbH, R&D CAS Drug Design FFMIndustriepark HoechstFrankfurt am MainGermany

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