New methods for efficient direct calculation of drug binding free energies

COMP 272

Michael R. Shirts, michael.shirts@columbia.edu, Department of Chemistry, Columbia University, New York, NY 10027, John D. Chodera, jchodera@gmail.com, Department of Chemistry, Stanford University, Clark Center, MC 5447, Stanford, CA 94305-5447, and Richard A. Friesner, Department of Chemistry and Center for Biomolecular Simulation, Columbia University, New York, NY 10027.
We present two methodological developments for computation of ligand binding free energies. The first is a maximum-likelihood method for combination of equilibrium simulations at different thermodynamic states, which is similar to the weighted histogram analysis method (WHAM), but removes the need for discretization of the energy into histograms. It additionally gives a direct estimate for the uncertainty, and is expected to be applicable for a wide range of chemical simulations. The second is a configuration bias method for free energy computation of ligand binding in implicit solvent, greatly saving the time required for side chain rearrangement. We demonstrate how these methods can be applied to free energy computations of ligand binding of FKBP-12 with several ligands.
 

Poster Session
6:00 PM-8:00 PM, Tuesday, August 21, 2007 BCEC -- Ballroom Foyer, Poster

Division of Computers in Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007