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Protein-ligand binding affinity by nonequilibrium free energy methods

Protein-ligand binding affinity by nonequilibrium free energy methods
Protein-ligand binding affinity by nonequilibrium free energy methods
Nonequilibrium (NE) free energy methods are embarrassingly parallel and may be very conveniently run on desktop computers using distributed computing 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 combinations of NE methods with various test systems were compared and protocols identified which yielded results as accurate as replica exchange thermodynamic integration (RETI). The NE approaches, however, lend themselves to extensive parallelization through the use of distributed computing.(1) Here the best performing of those NE protocols, a replica exchange method using Bennett’s acceptance ratio as the free energy estimator (RENE), is applied to two sets of congeneric inhibitors bound to neuraminidase and cyclooxygenase-2. These protein-ligand systems were originally studied with RETI,(2) giving results to which NE and RENE simulations are compared. These NE calculations were carried out on a large, highly distributed group of low-performance desktop computers 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 time.

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, equilibrium approaches.
1520-6106
14985-14992
Cossins, Benjamin P.
37b547b7-5f3a-45f8-918f-8f32206fc3de
Foucher, Sebastien
1b2db840-fb85-46ff-953e-2dadce996884
Edge, Colin M.
7cb32b1b-4e31-4d58-becc-c65d76dc9370
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Cossins, Benjamin P.
37b547b7-5f3a-45f8-918f-8f32206fc3de
Foucher, Sebastien
1b2db840-fb85-46ff-953e-2dadce996884
Edge, Colin M.
7cb32b1b-4e31-4d58-becc-c65d76dc9370
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5

Cossins, Benjamin P., Foucher, Sebastien, Edge, Colin M. and Essex, Jonathan W. (2008) Protein-ligand binding affinity by nonequilibrium free energy methods. The Journal of Physical Chemistry B, 112 (47), 14985-14992. (doi:10.1021/jp803533w).

Record type: Article

Abstract

Nonequilibrium (NE) free energy methods are embarrassingly parallel and may be very conveniently run on desktop computers using distributed computing 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 combinations of NE methods with various test systems were compared and protocols identified which yielded results as accurate as replica exchange thermodynamic integration (RETI). The NE approaches, however, lend themselves to extensive parallelization through the use of distributed computing.(1) Here the best performing of those NE protocols, a replica exchange method using Bennett’s acceptance ratio as the free energy estimator (RENE), is applied to two sets of congeneric inhibitors bound to neuraminidase and cyclooxygenase-2. These protein-ligand systems were originally studied with RETI,(2) giving results to which NE and RENE simulations are compared. These NE calculations were carried out on a large, highly distributed group of low-performance desktop computers 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 time.

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, equilibrium approaches.

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More information

Published date: 30 October 2008

Identifiers

Local EPrints ID: 149403
URI: http://eprints.soton.ac.uk/id/eprint/149403
ISSN: 1520-6106
PURE UUID: 155cfc98-f5ab-47d7-8b99-fee489155b4e
ORCID for Jonathan W. Essex: ORCID iD orcid.org/0000-0003-2639-2746

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Date deposited: 30 Apr 2010 08:52
Last modified: 10 Dec 2019 01:55

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