Explicit and implicit solvation binding free energies of FKBP-12

COMP 38

Michael R. Shirts, michael.shirts@columbia.edu, Department of Chemistry, Columbia University, New York, NY 10027, Guha Jayachandran, Department of Computer Science, Stanford University, Stanford, CA 94305, Christopher D. Snow, csnow@alum.mit.edu, Division of Chemistry and Chemical Engineering, California Institute of Technology, 331 Spalding, Pasadena, CA 91101, Vijay S. Pande, pande@stanford.edu, Departments of Chemistry and Structural Biology, Stanford University, Stanford, CA 94035, and Richard A. Friesner, Department of Chemistry and Center for Biomolecular Simulation, Columbia University, New York, NY 10027.
Recent developments in computational processing power and in theoretical methods have made it possible to compute absolute ligand binding free energies to a precision of under 1 kcal/mol. This level of precision makes it possible to separate errors in sampling from inadequacies of molecular mechanics force fields, and begins to make absolute binding free energy calculations relevant in drug design. We compare experimental free energies of binding of FKBP-12 with a number of ligands with extensive explicit solvent absolute free energies and with a novel configuration bias method for sampling protein complexes and ligands with continuum solvent, with many of the calculations being within 1 kcal/mol of experiment. The focus is primarily on the methodology that makes these types of calculations possible.
 

Drug Discovery
1:00 PM-5:05 PM, Sunday, August 19, 2007 BCEC -- 161, Oral

Division of Computers in Chemistry

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