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Free energies of binding from large-scale first-principles quantum mechanical calculations: application to ligand hydration energies

Free energies of binding from large-scale first-principles quantum mechanical calculations: application to ligand hydration energies
Free energies of binding from large-scale first-principles quantum mechanical calculations: application to ligand hydration energies
Schemes of increasing sophistication for obtaining free energies of binding have been developed over the years, where configurational sampling is used to include the all-important entropic contributions to the free energies. However, the quality of the results will also depend on the accuracy with which the intermolecular interactions are computed at each molecular configuration. In this context, the energy change associated with the rearrangement of electrons (electronic polarization and charge transfer) upon binding is a very important effect. Classical molecular mechanics force fields do not take this effect into account explicitly, and polarizable force fields and semiempirical quantum or hybrid quantum–classical (QM/MM) calculations are increasingly employed (at higher computational cost) to compute intermolecular interactions in free-energy schemes. In this work, we investigate the use of large-scale quantum mechanical calculations from first-principles as a way of fully taking into account electronic effects in free-energy calculations. We employ a one-step free-energy perturbation (FEP) scheme from a molecular mechanical (MM) potential to a quantum mechanical (QM) potential as a correction to thermodynamic integration calculations within the MM potential. We use this approach to calculate relative free energies of hydration of small aromatic molecules. Our quantum calculations are performed on multiple configurations from classical molecular dynamics simulations. The quantum energy of each configuration is obtained from density functional theory calculations with a near-complete psinc basis set on over 600 atoms using the ONETEP program
1520-6106
9478-9485
Fox, S.J.
a8957e8a-3086-4917-8575-eb0f9e8604cf
Pittock, Chris
0732d958-6ae6-48d8-81c8-3d17e32a0039
Tautermann, C.S.
8b8df865-08b1-407a-aab9-952445cd4414
Fox, T.
1d9ddbf8-6881-48cb-9abb-9c9c74a3f09a
Christ, C.
05764d73-ae11-4ea6-b5a6-00a0f8b95edd
Malcolm, N.O.J.
e11e1b0d-aa1e-4db2-813b-072d68356119
Essex, J. W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Skylaris, C.-K.
8f593d13-3ace-4558-ba08-04e48211af61
Fox, S.J.
a8957e8a-3086-4917-8575-eb0f9e8604cf
Pittock, Chris
0732d958-6ae6-48d8-81c8-3d17e32a0039
Tautermann, C.S.
8b8df865-08b1-407a-aab9-952445cd4414
Fox, T.
1d9ddbf8-6881-48cb-9abb-9c9c74a3f09a
Christ, C.
05764d73-ae11-4ea6-b5a6-00a0f8b95edd
Malcolm, N.O.J.
e11e1b0d-aa1e-4db2-813b-072d68356119
Essex, J. W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Skylaris, C.-K.
8f593d13-3ace-4558-ba08-04e48211af61

Fox, S.J., Pittock, Chris, Tautermann, C.S., Fox, T., Christ, C., Malcolm, N.O.J., Essex, J. W. and Skylaris, C.-K. (2013) Free energies of binding from large-scale first-principles quantum mechanical calculations: application to ligand hydration energies The Journal of Physical Chemistry B, 117, (32), pp. 9478-9485. (doi:10.1021/jp404518r).

Record type: Article

Abstract

Schemes of increasing sophistication for obtaining free energies of binding have been developed over the years, where configurational sampling is used to include the all-important entropic contributions to the free energies. However, the quality of the results will also depend on the accuracy with which the intermolecular interactions are computed at each molecular configuration. In this context, the energy change associated with the rearrangement of electrons (electronic polarization and charge transfer) upon binding is a very important effect. Classical molecular mechanics force fields do not take this effect into account explicitly, and polarizable force fields and semiempirical quantum or hybrid quantum–classical (QM/MM) calculations are increasingly employed (at higher computational cost) to compute intermolecular interactions in free-energy schemes. In this work, we investigate the use of large-scale quantum mechanical calculations from first-principles as a way of fully taking into account electronic effects in free-energy calculations. We employ a one-step free-energy perturbation (FEP) scheme from a molecular mechanical (MM) potential to a quantum mechanical (QM) potential as a correction to thermodynamic integration calculations within the MM potential. We use this approach to calculate relative free energies of hydration of small aromatic molecules. Our quantum calculations are performed on multiple configurations from classical molecular dynamics simulations. The quantum energy of each configuration is obtained from density functional theory calculations with a near-complete psinc basis set on over 600 atoms using the ONETEP program

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Published date: 2013
Organisations: Computational Systems Chemistry

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Local EPrints ID: 356349
URI: http://eprints.soton.ac.uk/id/eprint/356349
ISSN: 1520-6106
PURE UUID: 1e7c7374-5bf9-453b-a11e-b7c4d178af4b
ORCID for J. W. Essex: ORCID iD orcid.org/0000-0003-2639-2746

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Date deposited: 06 Sep 2013 08:36
Last modified: 20 Oct 2017 16:35

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Contributors

Author: S.J. Fox
Author: Chris Pittock
Author: C.S. Tautermann
Author: T. Fox
Author: C. Christ
Author: N.O.J. Malcolm
Author: J. W. Essex ORCID iD
Author: C.-K. Skylaris

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