Nonequilibriu
m (NE) free energy
methods are e
mbarrassingly parallel and
may be very conveniently run on desktop co
mputers using distributed co
mputing software. In recent years there has been a proliferation of NE
methods, but these approaches have barely, if at all, been used in the context of calculating protein−ligand binding free energies. In a recent study by these authors, different co
mbinations of NE
methods with various test syste
ms were co
mpared and protocols identified which yielded results as accurate as replica exchange ther
modyna
mic integration (RETI). The NE approaches, however, lend the
mselves to extensive parallelization through the use of distributed co
mputing.
(1) Here the best perfor
ming of those NE protocols, a replica exchange
method using Bennett’s acceptance ratio as the free energy esti
mator (RENE), is applied to two sets of congeneric inhibitors bound to neura
minidase and cyclooxygenase-2. These protein−ligand syste
ms were originally studied with RETI,
(2) giving results to which NE and RENE si
mulations are co
mpared. These NE calculations were carried out on a large, highly distributed group of low-perfor
mance desktop co
mputers which are part of a Condor pool.
(3) RENE was found to produce results of a predictive quality at least as good as RETI in less than half the wall clock ti
me. However, non-RE NE results were found to be far less predictive. In addition, the RENE
method successfully identified a localized region of rapidly changing free energy gradients without the need for prior investigation. These results suggest that the RENE protocol is appropriate for use in the context of predicting protein−ligand binding free energies and that it can offer advantages over conventional, equilibriu
m approaches.