An accurate description of solvation effects is of high importance in modeling biomolecular systems. Our main interest is to find an accurate yet efficient solvation model for semiempirical quantum-mechanical methods applicable to large protein-ligand complexes in the context of computer-aided drug design. We present a survey of readily available methods and a new reparametrization of the COSMO solvent model for PM6 and PM7 calculations in MOPAC. We have tested the reparametrized method on validation data sets of small drug-like molecules for which experimental solvation free energies are available as well as on a set of large model systems of the active site of carbonic anhydrase II interacting with a series of ligands for which experimental affinity values are known. In both cases, there is a significant improvement in accuracy after the reparametrization and the addition of a nonpolar term to the COSMO solvent model.

Department of Physical and Macromolecular Chemistry Faculty of Science Charles University Hlavova 8 128 40 Prague 2 Czech Republic

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences 166 10 Prague Czech Republic

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