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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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Translational correlationfunction for TIP4P-2005 between 0.0 and3.6 Å. The RDF between 0.0 and 3.6 Å from the bulk watersimulation of TIP4P-2005 (blue line) and an “effective RDF”computed for voxels at the given distance from the origin (red line).The effective RDF is calculated by first computing the distance betweenthe origin and the center of each voxel. Voxels at the same distancefrom the origin are then grouped together. The value of g(r) at each distance is calculated from the averagenumber of water molecules in the group of voxels at that distanceand their summed volume.
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fig2: Translational correlationfunction for TIP4P-2005 between 0.0 and3.6 Å. The RDF between 0.0 and 3.6 Å from the bulk watersimulation of TIP4P-2005 (blue line) and an “effective RDF”computed for voxels at the given distance from the origin (red line).The effective RDF is calculated by first computing the distance betweenthe origin and the center of each voxel. Voxels at the same distancefrom the origin are then grouped together. The value of g(r) at each distance is calculated from the averagenumber of water molecules in the group of voxels at that distanceand their summed volume.

Mentions: The simulation of bulk water also allows calculation of theexcessentropy (Sbulk). Numerous works have reportedthe excess translational entropy of bulk water based on IFST calculationsusing spherical polar coordinates.25,26,40−43 Due to bulk water being isotropic, the excess translationalentropy can be calculated from the radial distribution function (RDF).Using the RDF with a radial bin size of 0.1 Å, the excess translationalentropy in the first solvation shell (between 0.0 and 3.6 Å)is calculated to be −3.29 cal/mol/K for the TIP4P-2005 watermodel. This makes a contribution of +0.98 kcal/mol to the excess freeenergy. It is interesting to compare this with the translational entropybased on IFST calculations using a Cartesian coordinate system. Usingthe default grid resolution of 0.5 Å, the excess translationalentropy for voxels within the first solvation shell (between 0.0 and3.6 Å) is calculated to be −2.10 cal/mol/K. This makesa contribution of +0.63 kcal/mol to the excess free energy. The trueRDF and an “effective RDF” using the Cartesian coordinatesystem can be seen in Figure 2.


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)

Translational correlationfunction for TIP4P-2005 between 0.0 and3.6 Å. The RDF between 0.0 and 3.6 Å from the bulk watersimulation of TIP4P-2005 (blue line) and an “effective RDF”computed for voxels at the given distance from the origin (red line).The effective RDF is calculated by first computing the distance betweenthe origin and the center of each voxel. Voxels at the same distancefrom the origin are then grouped together. The value of g(r) at each distance is calculated from the averagenumber of water molecules in the group of voxels at that distanceand their summed volume.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Translational correlationfunction for TIP4P-2005 between 0.0 and3.6 Å. The RDF between 0.0 and 3.6 Å from the bulk watersimulation of TIP4P-2005 (blue line) and an “effective RDF”computed for voxels at the given distance from the origin (red line).The effective RDF is calculated by first computing the distance betweenthe origin and the center of each voxel. Voxels at the same distancefrom the origin are then grouped together. The value of g(r) at each distance is calculated from the averagenumber of water molecules in the group of voxels at that distanceand their summed volume.
Mentions: The simulation of bulk water also allows calculation of theexcessentropy (Sbulk). Numerous works have reportedthe excess translational entropy of bulk water based on IFST calculationsusing spherical polar coordinates.25,26,40−43 Due to bulk water being isotropic, the excess translationalentropy can be calculated from the radial distribution function (RDF).Using the RDF with a radial bin size of 0.1 Å, the excess translationalentropy in the first solvation shell (between 0.0 and 3.6 Å)is calculated to be −3.29 cal/mol/K for the TIP4P-2005 watermodel. This makes a contribution of +0.98 kcal/mol to the excess freeenergy. It is interesting to compare this with the translational entropybased on IFST calculations using a Cartesian coordinate system. Usingthe default grid resolution of 0.5 Å, the excess translationalentropy for voxels within the first solvation shell (between 0.0 and3.6 Å) is calculated to be −2.10 cal/mol/K. This makesa contribution of +0.63 kcal/mol to the excess free energy. The trueRDF and an “effective RDF” using the Cartesian coordinatesystem can be seen in Figure 2.

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