Direct calculation of the binding free energies of FKBP ligands using the Fujitsu BioServer massively parallel computer.

Hideaki Fujutani, Yoshiaki Tanida, Masakatsu Ito, Guha Jayachandran, Christopher D. Snow, Michael R. Shirts, Eric J. Sorin, and Vijay S. Pande
Journal of Chemical Physics (2005)

SUMMARY: Drug design calculations are generally very difficult. Here we show that calculations made previously on the Folding@home network are possible on a much smaller supercomputer system without loss of numerical precision.

TECHNICAL ABSTRACT: Direct calculations of the absolute binding free energies for eight FKBP ligands were performed using the Fujitsu BioServer massively parallel computer. Using latest version of the general AMBER force field (GAFF) for ligand model parameters and the Bennett acceptance ratio for computing free energy differences, we obtained an excellent linear fit between the calculated and experimental binding free energies. The RMS error from a linear fit is 0.4 kcal/mol for eight ligand complexes. In comparison with a previous study of the binding energies of these same eight ligand complexes, these results suggest that the use of improved model parameters can lead to more predictive binding estimates, and that these estimates can be obtained with significantly less computer time than previously thought. These findings make such direct methods more attractive for use in rational drug design.