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 R2 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.
Highlights
Inhomogeneous fluid solvation theory[1] (IFST) is a statistical mechanical framework for calculating the effect of a solute on the free energy of the surrounding solvent relative to its bulk state.[2]
Running average remains within 0.0002 kcal/mol of the final calculated value, yielding a final energy of a bulk water molecule (Ebulk) of −11.5813 kcal/mol for the TIP4P-2005 water model
This study addresses this issue by comparing hydration free energies from IFST with hydration free energies from free energy perturbation (FEP)
Summary
Inhomogeneous fluid solvation theory[1] (IFST) is a statistical mechanical framework for calculating the effect of a solute on the free energy of the surrounding solvent relative to its bulk state.[2]. Previous work on the solvation of methane suggests that these KSAs lead to reasonable results due to the cancellation of errors between more and less structured regions.[5] In this work, Sww was only calculated for pairs of voxels within 3.6 Å This is likely a good assumption for the translational contributions, which in bulk water are derived almost exclusively from the excluded volume and the first solvation shell.[25] The orientational contributions to Sww (and Sbulk) are expected to be underestimated, as only approximately 75% of the orientational entropy in bulk water is derived from the first solvation shell.[25,26] Calculations for gww(R) and gww(ωrel|R) were performed on pairs of voxels on the Cartesian grid from the 100 ns NPT simulation of bulk water at 300 K and 1 atm. We compare the predictions of FEP and IFST with Ben-Naim’s experimentally determined standard energy, entropy, and free energy of solvation These do not include the nonlocal contributions, which are excluded from our calculations.
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