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Assessment of nonequilibrium free energy methods

Assessment of nonequilibrium free energy methods
Assessment of nonequilibrium free energy methods
One of the factors preventing the general application of free energy methods in rational drug design remains the lack of sufficient computational resources. Many nonequilibrium (NE) free energy methods, however, are easily made embarrassingly parallel in comparison to equilibrium methods and may be conveniently run on desktop computers using distributed computing software. In recent years, there has been a proliferation of NE methods, but the general applicability of these approaches has not been determined. In this study, a subset including only those NE methods which are easily parallelised were considered for examination, with a view to their application to the prediction of protein?ligand binding affinities. A number of test systems were examined, including harmonic oscillator (HO) systems and the calculation of relative free energies of hydration of water?methane. The latter system uses identical potentials to the protein ligand case and is therefore an appropriate model system on which methods may be tested. As well as investigating existing protocols, a replica exchange NE approach was developed, which was found to offer advantages over conventional methods. It was found that Rosenbluth-based approaches to optimizing the NE work values used in NE free energy estimates were not consistent in the improvements in accuracy achieved and that, given their computational cost, the simple approach of taking each work value in an unbiased way is to be preferred. Of the two free energy estimators examined, Bennett’s acceptance ratio was the most consistent and is, therefore, to be preferred over the Jarzynski estimator. The recommended protocols may be run very efficiently within a distributed computing environment and are of similar accuracy and precision to equilibrium free energy methods.
1520-5207
5508-5519
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. (2009) Assessment of nonequilibrium free energy methods. The Journal of Physical Chemistry B, 113 (16), 5508-5519. (doi:10.1021/jp803532z).

Record type: Article

Abstract

One of the factors preventing the general application of free energy methods in rational drug design remains the lack of sufficient computational resources. Many nonequilibrium (NE) free energy methods, however, are easily made embarrassingly parallel in comparison to equilibrium methods and may be conveniently run on desktop computers using distributed computing software. In recent years, there has been a proliferation of NE methods, but the general applicability of these approaches has not been determined. In this study, a subset including only those NE methods which are easily parallelised were considered for examination, with a view to their application to the prediction of protein?ligand binding affinities. A number of test systems were examined, including harmonic oscillator (HO) systems and the calculation of relative free energies of hydration of water?methane. The latter system uses identical potentials to the protein ligand case and is therefore an appropriate model system on which methods may be tested. As well as investigating existing protocols, a replica exchange NE approach was developed, which was found to offer advantages over conventional methods. It was found that Rosenbluth-based approaches to optimizing the NE work values used in NE free energy estimates were not consistent in the improvements in accuracy achieved and that, given their computational cost, the simple approach of taking each work value in an unbiased way is to be preferred. Of the two free energy estimators examined, Bennett’s acceptance ratio was the most consistent and is, therefore, to be preferred over the Jarzynski estimator. The recommended protocols may be run very efficiently within a distributed computing environment and are of similar accuracy and precision to equilibrium free energy methods.

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Published date: 23 April 2009

Identifiers

Local EPrints ID: 149181
URI: http://eprints.soton.ac.uk/id/eprint/149181
ISSN: 1520-5207
PURE UUID: a0de7e13-271a-4df0-bc99-2c0219d32211
ORCID for Jonathan W. Essex: ORCID iD orcid.org/0000-0003-2639-2746

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Date deposited: 30 Apr 2010 08:56
Last modified: 20 Jul 2019 01:20

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