Estimation of Absolute Free Energies of Hydration Using Continuum Methods:  Accuracy of Partial Charge Models and Optimization of Nonpolar Contributions

Rizzo, Robert C.; Aynechi, Tiba; Case, David A.; Kuntz, Irwin D.

doi:10.1021/ct050097l

Cited by 164 publications

(260 citation statements)

References 58 publications

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“…Next, we explore a diverse solute set, containing 504 different small molecules (10,17,42). It is useful because of the availability of both experimental data and of extensive TIP3P explicit-solvent simulations (10).…”

Section: Resultsmentioning

confidence: 99%

“…Aqueous solvation has been modeled at different levels, ranging from detailed quantum mechanics simulations of few-molecule clusters (1,2), to faster classical simulations using up to tens of thousands of explicit molecules (3)(4)(5)(6)(7)(8)(9)(10), to very fast models in which water is treated implicitly as a simple uniform continuous medium (11)(12)(13)(14)(15)(16)(17). For large computations, such as those in typical biomolecule simulations, explicit-water modeling can be slow and expensive, so it is common to use implicit water instead.…”

mentioning

confidence: 99%

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Modeling aqueous solvation with semi-explicit assembly

Fennell¹,

Kehoe

Dill³

2011

Proc. Natl. Acad. Sci. U.S.A.

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We describe a computational solvation model called semi-explicit assembly (SEA). SEA water captures much of the physics of explicitsolvent models but with computational speeds approaching those of implicit-solvent models. We use an explicit-water model to precompute properties of water solvation shells around simple spheres, then assemble a solute's solvation shell by combining the shells of these spheres. SEA improves upon implicit-solvent models of solvation free energies by accounting for local solute curvature, accounting for near-neighbor nonadditivities, and treating water's dipole as being asymmetrical with respect to positive or negative solute charges. SEA does not involve parameter fitting, because parameters come from the given underlying explicitsolvation model. SEA is about as accurate as explicit simulations as shown by comparisons against four different homologous alkyl series, a set of 504 varied solutes, solutes taken retrospectively from two solvation-prediction events, and a hypothetical polarsolute series, and SEA is about 100-fold faster than Poisson-Boltzmann calculations.free energy | implicit solvent | transfer W e describe here an approach for computing the free energies of solvation of solutes in water. Aqueous solvation has been modeled at different levels, ranging from detailed quantum mechanics simulations of few-molecule clusters (1, 2), to faster classical simulations using up to tens of thousands of explicit molecules (3-10), to very fast models in which water is treated implicitly as a simple uniform continuous medium (11)(12)(13)(14)(15)(16)(17). For large computations, such as those in typical biomolecule simulations, explicit-water modeling can be slow and expensive, so it is common to use implicit water instead. However, implicit models often require trade-offs in the physics that can limit their accuracies. For example, water is typically treated as a continuum rather than individual particles, and this neglects discrete microscopic effects; nonpolar solvation effects are often assumed to depend only on surface area A (expressed as γA), and not on detailed dispersive interactions and collective consequences of solute shape (18)(19)(20).It would be useful to have a computational model of water that is both fast-approaching the speeds of the fastest implicitsolvent models-and that captures the physics and the transferability of explicit-solvent models. Toward this goal, various improvements of implicit models have been introduced (21, 22), explicit solvents have been coarse-grained (23, 24), and hybrid explicit-implicit models have been developed (25)(26)(27)(28)(29). Here, we take a different approach. We precompute solvation properties of water in explicit-solvent simulations of simple spheres, which we then apply in summations over assemblies about arbitrary solutes. As the details of the solvation response come entirely from the physics of an explicit solvent, this model lacks free parameters from statistical fits to solute molecular transfer free energies, resulting in a ...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Modeling aqueous solvation with semi-explicit assembly

Fennell¹,

Kehoe

Dill³

2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Radii for bromine and iodine for the "bondi", "mbondi", and "mbondi2" radii schemes were set to 1.85 and 1.98 Å, respectively, as in other work. 19 …”

Section: Simulation Setupmentioning

confidence: 99%

Treating Entropy and Conformational Changes in Implicit Solvent Simulations of Small Molecules

2008

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Implicit solvent models are increasingly popular for estimating aqueous solvation (hydration) free energies in molecular simulations and other applications. In many cases, parameters for these models are derived to reproduce experimental values for small molecule hydration free energies. Often, these hydration free energies are computed for a single solute conformation, neglecting solute conformational changes upon solvation. Here, we incorporate these effects using alchemical free energy methods. We find significant errors when hydration free energies are estimated using only a single solute conformation, even for relatively small, simple, rigid solutes. For example, we find conformational entropy (TΔS) changes of up to 2.3 kcal/mol upon hydration. Interestingly, these changes in conformational entropy correlate poorly (R 2 = 0.03) with the number of rotatable bonds. The present study illustrates that implicit solvent modeling can be improved by eliminating the approximation that solutes are rigid.

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“…Thus, the dipole moment of N,N-dimethylaniline in cyclohexane is 1.5 D 30 and that of nitrobenzene is 4.0 D. 31 Experimentally, nitrobenzene is more strongly hydrated, with a hydration free energy of −4.12 kcal/mol; N,N-dimethylaniline has a hydration free energy of −3.45 kcal/mol, a difference of 0.67 kcal/mol. 32 Because of the large difference in dipole moments, the Poisson-Boltzmann equation predicts a difference of 4.6 kcal/mol between the two hydration free energies. 29 Given the large experimental difference in dipole moment, why are the hydration free energies so similar?…”

Section: Real Solutes Also Appear To Have Hydration Free Energy Asymmmentioning

confidence: 99%

Charge Asymmetries in Hydration of Polar Solutes

et al. 2008

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We study the solvation of polar molecules in water. The center of water's dipole moment is offset from its steric center. In common water models, the Lennard-Jones center is closer to the negatively charged oxygen than to the positively charged hydrogens. This asymmetry of water's charge sites leads to different hydration free energies of positive versus negative ions of the same size. Here, we explore these hydration effects for some hypothetical neutral solutes, and two real solutes, with molecular dynamics simulations using several different water models. We find that, like ions, polar solutes are solvated differently in water depending on the sign of the partial charges. Solutes having a large negative charge balancing diffuse positive charges are preferentially solvated relative to those having a large positive charge balancing diffuse negative charges. Asymmetries in hydration free energies can be as large as 10 kcal/mol for neutral benzene-sized solutes. These asymmetries are mainly enthalpic, arising primarily from the first solvation shell water structure. Such effects are not readily captured by implicit solvent models, which respond symmetrically with respect to charge.

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Estimation of Absolute Free Energies of Hydration Using Continuum Methods: Accuracy of Partial Charge Models and Optimization of Nonpolar Contributions

Cited by 164 publications

References 58 publications

Modeling aqueous solvation with semi-explicit assembly

Modeling aqueous solvation with semi-explicit assembly

Treating Entropy and Conformational Changes in Implicit Solvent Simulations of Small Molecules

Charge Asymmetries in Hydration of Polar Solutes

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