Comparison of charge models for fixed-charge forcefields: Small molecule hydration free energies in explicit solvent

COMP 213

Élise Dumont, elise.dumont@ens.fr, Laboratoire de Chimie Théorique, Paris, France, David L. Mobley, dmobley@maxwell.compbio.ucsf.edu, Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Box 2240, San Francisco, CA 95616, John D. Chodera, jchodera@ugcs.caltech.edu, Graduate Group in Biophysics, University of California, San Francisco, UCSF Mission Bay, Box 2240, 600 16th Street, San Francisco, CA 94143-2280, and Ken A. Dill, dill@maxwell.compbio.ucsf.edu, Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA 94143.
The method by which partial charges are computed for small molecules in fixed-charged molecular mechanics forcefields is of tremendous importance for ligand binding free energy calculations, as small differences in the partial charge distribution can have large effects on computed binding affinities. There are many choices for obtaining partial charges, including the level of quantum theory, the use of a continuum reaction field, and the method by which partial charges are computed from the electron density. We consider several combinations of these choices and test how well the resulting charge models can reproduce experimental free energies of hydration for a set of small molecules, using the AMBER GAFF forcefield and two different fixed-charge water models (TIP3P and TIP4P-Ew). As the calculation of binding free energies involves removal of the ligand from solvent, we expect accurate reproduction of hydration free energies is likely essential for computing accurate binding free energies.
 

Poster Session
6:00 PM-8:00 PM, Tuesday, 12 September 2006 Moscone Center -- Hall D, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, 11 September 2006 Moscone Center -- Hall D, Sci-Mix

Division of Computers in Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006