### Abstract

We report a method to dramatically improve the accuracy of hydration free energies (HFE) calculated by the 1D and 3D reference interaction site models (RISM) of molecular integral equation theory. It is shown that the errors in HFEs calculated by RISM approaches using the Gaussian fluctuations (GF) free energy functional are not random, but can be decomposed into linear combination of contributions from different structural elements of molecules (number of double bonds, number of OH groups, etc.). Therefore, by combining RISM/GF with cheminformatics, one can develop an accurate method for HFE prediction. We call this approach the structural description correction model (SDC) (Ratkova et al. J. Phys. Chem. B 2010, 114, 12068). In this work, we investigated the prediction quality of the SDC model combined with 1D and 3D RISM approaches. In parallel, we analyzed the computational performance of these two methods. The SD C model parameters were obtained by fitting against a training set of 53 simple organic molecules. To demonstrate that the values of these parameters were transferable between different classes of molecules, the models were tested against 98 more complex molecules (including 38 polyfragment compounds). The results show that the 3D RISM/SDC model predicts the HFEs with very good accuracy (RMSE of 0.47 kcal/mol), while the ID RISM approach provides only moderate accuracy (RMSE of 1.96 kcal/mol). However, a single ID RISM/SDC calculation takes only a few seconds on a PC, whereas a single 3D RISM/SDC HFE calculation is approximately 100 times more computationally expensive. Therefore, we suggest that one should use the 1D RISM/SDC model for large-scale high-throughput screening of molecular hydration properties, while further refinement of these properties for selected compounds should be carried out with the more computationally expensive but more accurate 3D RISM/SDC model.

Language | English |
---|---|

Pages | 6011-6022 |

Number of pages | 12 |

Journal | Journal of Physical Chemistry B |

Volume | 115 |

Issue number | 19 |

DOIs | |

Publication status | Published - 19 May 2011 |

### Fingerprint

### Keywords

- integral-equation theory
- free energy calculations
- solvation free energy
- atom force-field
- aqueous-solutions
- conformational stability
- efficient generation
- molecular dynamics
- polar molecules
- AM1-BCC model

### Cite this

*Journal of Physical Chemistry B*,

*115*(19), 6011-6022. https://doi.org/10.1021/jp111271c

}

*Journal of Physical Chemistry B*, vol. 115, no. 19, pp. 6011-6022. https://doi.org/10.1021/jp111271c

**Hydration thermodynamics using the reference interaction site model : speed or accuracy?** / Frolov, Andrey I.; Ratkova, Ekaterina L.; Palmer, David; Fedorov, Maxim V.

Research output: Contribution to journal › Article

TY - JOUR

T1 - Hydration thermodynamics using the reference interaction site model

T2 - Journal of Physical Chemistry B

AU - Frolov, Andrey I.

AU - Ratkova, Ekaterina L.

AU - Palmer, David

AU - Fedorov, Maxim V.

PY - 2011/5/19

Y1 - 2011/5/19

N2 - We report a method to dramatically improve the accuracy of hydration free energies (HFE) calculated by the 1D and 3D reference interaction site models (RISM) of molecular integral equation theory. It is shown that the errors in HFEs calculated by RISM approaches using the Gaussian fluctuations (GF) free energy functional are not random, but can be decomposed into linear combination of contributions from different structural elements of molecules (number of double bonds, number of OH groups, etc.). Therefore, by combining RISM/GF with cheminformatics, one can develop an accurate method for HFE prediction. We call this approach the structural description correction model (SDC) (Ratkova et al. J. Phys. Chem. B 2010, 114, 12068). In this work, we investigated the prediction quality of the SDC model combined with 1D and 3D RISM approaches. In parallel, we analyzed the computational performance of these two methods. The SD C model parameters were obtained by fitting against a training set of 53 simple organic molecules. To demonstrate that the values of these parameters were transferable between different classes of molecules, the models were tested against 98 more complex molecules (including 38 polyfragment compounds). The results show that the 3D RISM/SDC model predicts the HFEs with very good accuracy (RMSE of 0.47 kcal/mol), while the ID RISM approach provides only moderate accuracy (RMSE of 1.96 kcal/mol). However, a single ID RISM/SDC calculation takes only a few seconds on a PC, whereas a single 3D RISM/SDC HFE calculation is approximately 100 times more computationally expensive. Therefore, we suggest that one should use the 1D RISM/SDC model for large-scale high-throughput screening of molecular hydration properties, while further refinement of these properties for selected compounds should be carried out with the more computationally expensive but more accurate 3D RISM/SDC model.

AB - We report a method to dramatically improve the accuracy of hydration free energies (HFE) calculated by the 1D and 3D reference interaction site models (RISM) of molecular integral equation theory. It is shown that the errors in HFEs calculated by RISM approaches using the Gaussian fluctuations (GF) free energy functional are not random, but can be decomposed into linear combination of contributions from different structural elements of molecules (number of double bonds, number of OH groups, etc.). Therefore, by combining RISM/GF with cheminformatics, one can develop an accurate method for HFE prediction. We call this approach the structural description correction model (SDC) (Ratkova et al. J. Phys. Chem. B 2010, 114, 12068). In this work, we investigated the prediction quality of the SDC model combined with 1D and 3D RISM approaches. In parallel, we analyzed the computational performance of these two methods. The SD C model parameters were obtained by fitting against a training set of 53 simple organic molecules. To demonstrate that the values of these parameters were transferable between different classes of molecules, the models were tested against 98 more complex molecules (including 38 polyfragment compounds). The results show that the 3D RISM/SDC model predicts the HFEs with very good accuracy (RMSE of 0.47 kcal/mol), while the ID RISM approach provides only moderate accuracy (RMSE of 1.96 kcal/mol). However, a single ID RISM/SDC calculation takes only a few seconds on a PC, whereas a single 3D RISM/SDC HFE calculation is approximately 100 times more computationally expensive. Therefore, we suggest that one should use the 1D RISM/SDC model for large-scale high-throughput screening of molecular hydration properties, while further refinement of these properties for selected compounds should be carried out with the more computationally expensive but more accurate 3D RISM/SDC model.

KW - integral-equation theory

KW - free energy calculations

KW - solvation free energy

KW - atom force-field

KW - aqueous-solutions

KW - conformational stability

KW - efficient generation

KW - molecular dynamics

KW - polar molecules

KW - AM1-BCC model

U2 - 10.1021/jp111271c

DO - 10.1021/jp111271c

M3 - Article

VL - 115

SP - 6011

EP - 6022

JO - Journal of Physical Chemistry B

JF - Journal of Physical Chemistry B

SN - 1520-6106

IS - 19

ER -