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Assessing the accuracy of inhomogeneous fluid solvation theory in predicting hydration free energies of simple solutes.

Huggins DJ, Payne MC - J Phys Chem B (2013)

Bottom Line: IFST has found wide application in understanding hydration phenomena in biological systems, but quantitative applications have not been comprehensively assessed.The results demonstrate that IFST shows good agreement with FEP, with an R(2) coefficient of determination of 0.99 and a mean unsigned difference of 0.7 kcal/mol.Further work is necessary before IFST can be extended to yield accurate predictions of binding free energies, but the work presented here demonstrates its potential.

View Article: PubMed Central - PubMed

Affiliation: Theory of Condensed Matter Group, Cavendish Laboratory, University of Cambridge, 19 J J Thomson Avenue, Cambridge CB3 0HE, UK. djh210@cam.ac.uk

ABSTRACT
Accurate prediction of hydration free energies is a key objective of any free energy method that is applied to modeling and understanding interactions in the aqueous phase. Inhomogeneous fluid solvation theory (IFST) is a statistical mechanical method for calculating solvation free energies by quantifying the effect of a solute acting as a perturbation to bulk water. IFST has found wide application in understanding hydration phenomena in biological systems, but quantitative applications have not been comprehensively assessed. In this study, we report the hydration free energies of six simple solutes calculated using IFST and independently using free energy perturbation (FEP). This facilitates a validation of IFST that is independent of the accuracy of the force field. The results demonstrate that IFST shows good agreement with FEP, with an R(2) coefficient of determination of 0.99 and a mean unsigned difference of 0.7 kcal/mol. However, sampling is a major issue that plagues IFST calculations and the results suggest that a histogram method may require prohibitively long simulations to achieve convergence of the entropies, for bin sizes which effectively capture the underlying probability distributions. Results also highlight the sensitivity of IFST to the reference interaction energy of a water molecule in bulk, with a difference of 0.01 kcal/mol changing the predicted hydration free energies by approximately 2.4 kcal/mol for the systems studied here. One of the major advantages of IFST over perturbation methods such as FEP is that the systems are spatially decomposed to consider the contribution of specific regions to the total solvation free energies. Visualizing these contributions can yield detailed insights into solvation thermodynamics. An insight from this work is the identification and explanation of regions with unfavorable free energy density relative to bulk water. These regions contribute unfavorably to the hydration free energy. Further work is necessary before IFST can be extended to yield accurate predictions of binding free energies, but the work presented here demonstrates its potential.

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Cumulative contributions to ΔEIFST, ΔSIFST, and ΔGIFST for acetamide at increasing distances fromthe origin:the cumulative contributions to ΔEIFST (blue diamonds), TΔSIFST (red squares), and ΔGIFST (green triangles) for acetamide between 0.0 and 12.0 Å fromthe origin.
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fig4: Cumulative contributions to ΔEIFST, ΔSIFST, and ΔGIFST for acetamide at increasing distances fromthe origin:the cumulative contributions to ΔEIFST (blue diamonds), TΔSIFST (red squares), and ΔGIFST (green triangles) for acetamide between 0.0 and 12.0 Å fromthe origin.

Mentions: We then moved on to consider thesolute–water systems. Akey question that we have previously attempted to address is the sizeof the solvation shell around a solute that is affected by its presence.13,23 However, previous studies were incomplete because they consideredthe per voxel values of ΔEIFST,ΔSIFST, and ΔGIFST with increasing distance from the origin rather thanthe total ΔEIFST, ΔSIFST, and ΔGIFST. These total values are affected by the volume increasing with thecube of the distance from the origin and are more revealing. We havecalculated these values for the six solutes to more thoroughly addressthis issue. The results can be seen in Figure 4 for acetamide.


Assessing the accuracy of inhomogeneous fluid solvation theory in predicting hydration free energies of simple solutes.

Huggins DJ, Payne MC - J Phys Chem B (2013)

Cumulative contributions to ΔEIFST, ΔSIFST, and ΔGIFST for acetamide at increasing distances fromthe origin:the cumulative contributions to ΔEIFST (blue diamonds), TΔSIFST (red squares), and ΔGIFST (green triangles) for acetamide between 0.0 and 12.0 Å fromthe origin.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756531&req=5

fig4: Cumulative contributions to ΔEIFST, ΔSIFST, and ΔGIFST for acetamide at increasing distances fromthe origin:the cumulative contributions to ΔEIFST (blue diamonds), TΔSIFST (red squares), and ΔGIFST (green triangles) for acetamide between 0.0 and 12.0 Å fromthe origin.
Mentions: We then moved on to consider thesolute–water systems. Akey question that we have previously attempted to address is the sizeof the solvation shell around a solute that is affected by its presence.13,23 However, previous studies were incomplete because they consideredthe per voxel values of ΔEIFST,ΔSIFST, and ΔGIFST with increasing distance from the origin rather thanthe total ΔEIFST, ΔSIFST, and ΔGIFST. These total values are affected by the volume increasing with thecube of the distance from the origin and are more revealing. We havecalculated these values for the six solutes to more thoroughly addressthis issue. The results can be seen in Figure 4 for acetamide.

Bottom Line: IFST has found wide application in understanding hydration phenomena in biological systems, but quantitative applications have not been comprehensively assessed.The results demonstrate that IFST shows good agreement with FEP, with an R(2) coefficient of determination of 0.99 and a mean unsigned difference of 0.7 kcal/mol.Further work is necessary before IFST can be extended to yield accurate predictions of binding free energies, but the work presented here demonstrates its potential.

View Article: PubMed Central - PubMed

Affiliation: Theory of Condensed Matter Group, Cavendish Laboratory, University of Cambridge, 19 J J Thomson Avenue, Cambridge CB3 0HE, UK. djh210@cam.ac.uk

ABSTRACT
Accurate prediction of hydration free energies is a key objective of any free energy method that is applied to modeling and understanding interactions in the aqueous phase. Inhomogeneous fluid solvation theory (IFST) is a statistical mechanical method for calculating solvation free energies by quantifying the effect of a solute acting as a perturbation to bulk water. IFST has found wide application in understanding hydration phenomena in biological systems, but quantitative applications have not been comprehensively assessed. In this study, we report the hydration free energies of six simple solutes calculated using IFST and independently using free energy perturbation (FEP). This facilitates a validation of IFST that is independent of the accuracy of the force field. The results demonstrate that IFST shows good agreement with FEP, with an R(2) coefficient of determination of 0.99 and a mean unsigned difference of 0.7 kcal/mol. However, sampling is a major issue that plagues IFST calculations and the results suggest that a histogram method may require prohibitively long simulations to achieve convergence of the entropies, for bin sizes which effectively capture the underlying probability distributions. Results also highlight the sensitivity of IFST to the reference interaction energy of a water molecule in bulk, with a difference of 0.01 kcal/mol changing the predicted hydration free energies by approximately 2.4 kcal/mol for the systems studied here. One of the major advantages of IFST over perturbation methods such as FEP is that the systems are spatially decomposed to consider the contribution of specific regions to the total solvation free energies. Visualizing these contributions can yield detailed insights into solvation thermodynamics. An insight from this work is the identification and explanation of regions with unfavorable free energy density relative to bulk water. These regions contribute unfavorably to the hydration free energy. Further work is necessary before IFST can be extended to yield accurate predictions of binding free energies, but the work presented here demonstrates its potential.

Show MeSH
Related in: MedlinePlus