S. A. Martins has contributed to the data acquisition of all the results provided with this manuscript. She has also given her input to the analysis and interpretation of the outcome of this study, and has contributed to the drafting and revision of the manuscript. S. F. Sousa has contributed to the design of the research presented with this manuscript. Additionally, he has also contributed to the interpretation and revision of the obtained data and to the critical revision of the paper and to the approval of submitted version.
Comparative assessment of computational methods for the determination of solvation free energies in alcohol-based molecules
Article first published online: 1 MAR 2013
Copyright © 2013 Wiley Periodicals, Inc.
Journal of Computational Chemistry
Volume 34, Issue 15, pages 1354–1362, 5 June 2013
How to Cite
Martins, S. A. and Sousa, S. F. (2013), Comparative assessment of computational methods for the determination of solvation free energies in alcohol-based molecules. J. Comput. Chem., 34: 1354–1362. doi: 10.1002/jcc.23264
- Issue published online: 25 APR 2013
- Article first published online: 1 MAR 2013
- Manuscript Accepted: 8 FEB 2013
- Manuscript Revised: 24 JAN 2013
- Manuscript Received: 23 NOV 2012
- FCT. Grant Numbers: projects PTDC/QUI-QUI/100372/2008, Pest-C/EQB/LA0006/2011), SFRH/BD/46867/2008
- hydration free energies;
- polarizable continuum models;
- thermodynamic integration;
- binding free energies;
- generalized Born;
The determination of differences in solvation free energies between related drug molecules remains an important challenge in computational drug optimization, when fast and accurate calculation of differences in binding free energy are required. In this study, we have evaluated the performance of five commonly used polarized continuum model (PCM) methodologies in the determination of solvation free energies for 53 typical alcohol and alkane small molecules. In addition, the performance of these PCM methods, of a thermodynamic integration (TI) protocol and of the Poisson–Boltzmann (PB) and generalized Born (GB) methods, were tested in the determination of solvation free energies changes for 28 common alkane-alcohol transformations, by the substitution of an hydrogen atom for a hydroxyl substituent. The results show that the solvation model D (SMD) performs better among the PCM-based approaches in estimating solvation free energies for alcohol molecules, and solvation free energy changes for alkane-alcohol transformations, with an average error below 1 kcal/mol for both quantities. However, for the determination of solvation free energy changes on alkane-alcohol transformation, PB and TI yielded better results. TI was particularly accurate in the treatment of hydroxyl groups additions to aromatic rings (0.53 kcal/mol), a common transformation when optimizing drug-binding in computer-aided drug design. © 2013 Wiley Periodicals, Inc.