On the use of orientational restraints and symmetry corrections in alchemical free energy calculations.

ABSTRACT: Alchemical free energy calculations are becoming a useful tool for calculating absolute binding free energies of small molecule ligands to proteins. Here, we find that the presence of multiple metastable ligand orientations can cause convergence problems when distance restraints alone are used. We demonstrate that the use of orientational restraints can greatly accelerate the convergence of these calculations. However, even with this acceleration, we find that sufficient sampling requires substantially longer simulations than are used in many published protocols. To further accelerate convergence, we introduce a new method of configuration space decomposition by orientation which reduces required simulation lengths by at least a factor of 5 in the cases examined. Our method is easily paral

SUBMITTER: Mobley DL 

PROVIDER: S-EPMC3583553 | biostudies-literature | 2006 Aug

REPOSITORIES: biostudies-literature