Free energy grids: a practical qualitative application of free energy perturbation to ligand design using the OWFEG method.

摘要

Traditional window-based free energy calculations can precisely determine the free energy corresponding to a molecular change of interest. However, calculations performed in this fashion are typically slow and resource-intensive, which renders them less than ideal for drug design. To circumvent this drawback, a new approximate free energy method, OWFEG, has been developed and tested. OWFEG replaces the exact free energy calculation for a single change with a set of approximate calculations for a grid of possible changes surrounding a molecule. One of the key features of OWFEG is that a floating independent reference frame (FIRF) is used, so that each grid point moves with the region of the molecule to which it is closest. In this way, this approach has been made applicable to flexible molecules. OWFEG is applied to two model systems and then to the FKBP-12.FK506 protein-ligand complex. On the basis of the results of these tests, this approximate method shows promise as a predictive tool for drug design.