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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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Convergenceof Ebulk for a 100 ns simulationof bulk TIP4P-2005 water: the running average of Ebulk for a 100 ns NPT simulation of bulk TIP4P-2005 waterat 300 K and 1 atm. The running average is calculated for 400 blocksof 250 ps. Each block is the average potential energy per water moleculetaken from 2500 samples with one every 100 fs.
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fig1: Convergenceof Ebulk for a 100 ns simulationof bulk TIP4P-2005 water: the running average of Ebulk for a 100 ns NPT simulation of bulk TIP4P-2005 waterat 300 K and 1 atm. The running average is calculated for 400 blocksof 250 ps. Each block is the average potential energy per water moleculetaken from 2500 samples with one every 100 fs.

Mentions: The simulation of bulk water is a key part of this work, as ΔEIFST depends critically upon the calculatedvalue of Ebulk. This is because the volumeof solvent we are considering (voxels within 12.0 Å of the origin)contains approximately 240 water molecules. Thus, a difference of0.01 kcal/mol in Ebulk leads to a differenceof 2.4 kcal/mol in ΔEIFST and ΔEFEP. This is significant in the context of predictingsolvation free energies. A simple calculation suggests that Ebulk must be correctly converged to within 0.0002kcal/mol for ΔEIFST and ΔEFEP to be correctly calculated to within 0.1kcal/mol. This extreme dependence means that it is thus vital thatthe calculation of Ebulk is converged.Figure 1 shows the convergence of Ebulk for the 100.0 ns NPT simulation. After approximately75 ns, the running average remains within 0.0002 kcal/mol of the finalcalculated value, yielding a final Ebulk of −11.5813 kcal/mol for the TIP4P-2005 water model.


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)

Convergenceof Ebulk for a 100 ns simulationof bulk TIP4P-2005 water: the running average of Ebulk for a 100 ns NPT simulation of bulk TIP4P-2005 waterat 300 K and 1 atm. The running average is calculated for 400 blocksof 250 ps. Each block is the average potential energy per water moleculetaken from 2500 samples with one every 100 fs.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Convergenceof Ebulk for a 100 ns simulationof bulk TIP4P-2005 water: the running average of Ebulk for a 100 ns NPT simulation of bulk TIP4P-2005 waterat 300 K and 1 atm. The running average is calculated for 400 blocksof 250 ps. Each block is the average potential energy per water moleculetaken from 2500 samples with one every 100 fs.
Mentions: The simulation of bulk water is a key part of this work, as ΔEIFST depends critically upon the calculatedvalue of Ebulk. This is because the volumeof solvent we are considering (voxels within 12.0 Å of the origin)contains approximately 240 water molecules. Thus, a difference of0.01 kcal/mol in Ebulk leads to a differenceof 2.4 kcal/mol in ΔEIFST and ΔEFEP. This is significant in the context of predictingsolvation free energies. A simple calculation suggests that Ebulk must be correctly converged to within 0.0002kcal/mol for ΔEIFST and ΔEFEP to be correctly calculated to within 0.1kcal/mol. This extreme dependence means that it is thus vital thatthe calculation of Ebulk is converged.Figure 1 shows the convergence of Ebulk for the 100.0 ns NPT simulation. After approximately75 ns, the running average remains within 0.0002 kcal/mol of the finalcalculated value, yielding a final Ebulk of −11.5813 kcal/mol for the TIP4P-2005 water model.

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