Solubility of nonelectrolytes in polar solvents. V. Estimation of the solubility of aliphatic monofunctional compounds in water using a molecular surface area approach

Amidon, Gordon L.; Yalkowsky, Samuel H.; Anik, Shabbir T.; Valvani, Shri C.

doi:10.1021/j100588a008

Cited by 152 publications

(73 citation statements)

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“…⌬G elec,desolv is calculated according to the GB-MV2 generalized Born model. ⌬G np,desolv is assumed to be proportional to the solvent-accessible surface area that is buried upon complexation (54,55); i.e. ⌬G np,desolv ϭ ϫ ⌬SASA, with ϭ 0.0072 kcal/(mol Å 2 ) (56 -58).…”

Section: Methodsmentioning

confidence: 99%

Combined Simulation and Mutagenesis Analyses Reveal the Involvement of Key Residues for Peroxisome Proliferator-activated Receptorα Helix 12 Dynamic Behavior

Michalik

Zoete

Krey

et al. 2007

Journal of Biological Chemistry

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The dynamic properties of helix 12 in the ligand binding domain of nuclear receptors are a major determinant of AF-2 domain activity. We investigated the molecular and structural basis of helix 12 mobility, as well as the involvement of individual residues with regard to peroxisome proliferator-activated receptor ␣ (PPAR␣) constitutive and ligand-dependent transcriptional activity. Functional assays of the activity of PPAR␣ helix 12 mutants were combined with free energy molecular dynamics simulations. The agreement between the results from these approaches allows us to make robust claims concerning the mechanisms that govern helix 12 functions. Our data support a model in which PPAR␣ helix 12 transiently adopts a relatively stable active conformation even in the absence of a ligand. This conformation provides the interface for the recruitment of a coactivator and results in constitutive activity. The receptor agonists stabilize this conformation and increase PPAR␣ transcription activation potential. Finally, we disclose important functions of residues in PPAR␣ AF-2, which determine the positioning of helix 12 in the active conformation in the absence of a ligand. Substitution of these residues suppresses PPAR␣ constitutive activity, without changing PPAR␣ ligand-dependent activation potential.The three peroxisome proliferator-activated receptor isotypes (PPARs) 5 ␣, ␤/␦, and ␥ (NR1C1, NR1C2, and NR1C3, respectively (1)) form a distinct subfamily of nuclear hormone receptors (2, 3). They are key regulators of lipid and glucose homeostasis, inflammation, cancer, and tissue repair (4 -7). The effect of PPARs on the expression of their target genes results from three events: recognition and binding of the receptor to response sequences in the promoter of the target genes, ligand binding, and co-repressor/co-activator exchange. Two regions exhibit a high degree of similarity in all members of the superfamily, namely the DNA binding domain, which is located toward the N terminus, and the ligand and cofactor binding domain (LBD). Ligand binding by the receptor is generally thought to be the trigger for transcriptional activation, but alternative mechanisms such as modulation of receptor activity by phosphorylation have also been reported (8, 9). Particularly, PPAR␣ shows a high constitutive activity, but the molecular basis and role in vivo of this activity are unclear (10, 11). A wide variety of natural or synthetic compounds, including fatty acids and eicosanoids, was identified as PPAR ligands (12-15). Among the synthetic ligands, the lipid-lowering drugs fibrates and the insulin sensitizers thiazolidinediones are PPAR␣ and PPAR␥ agonists, respectively; these underscore the important role of PPARs as therapeutic targets. Besides its role in ligand binding and dimerization, the LBD is also the site of the major and ligand-dependent transcriptional activation function of the nuclear receptors, called the activation function 2 (AF-2) domain (16). The PPAR LBD consists of 12 ␣ helices forming the characteristic three-l...

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Section: Methodsmentioning

confidence: 99%

Combined Simulation and Mutagenesis Analyses Reveal the Involvement of Key Residues for Peroxisome Proliferator-activated Receptorα Helix 12 Dynamic Behavior

Michalik

Zoete

Krey

et al. 2007

Journal of Biological Chemistry

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confidence: 99%

“…The linear correlation of the free energy of solvation with the accessible surface area has been used to estimate solubilities of hydrocarbons and monofunctional aliphatic compounds in water (16,22). The additivity of group contributions has been tested on computations of the heat capacity of nonelectrolytes in aqueous solution (19,(22)(23)(24). METHOD Accessible surface areas were computed for seven classes of atoms or groups, listed in Table 1-namely, (i) aliphatic -CH3, -CH2-, and \ CH-groups (considered as one class, in order to avoid an increase in the number of parameters), (it) aromatic =CH-groups, (iii) hydroxyl -OH groups, (iv) amide and amine -NH-and -NH2 groups, (v) carboxyl and carbonyl/C= carbons, (Vi) carboxyl and carbonyl 0= oxygens, and (vii) sulfur S-atoms and thiol -SH groups.…”

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confidence: 99%

Accessible surface areas as a measure of the thermodynamic parameters of hydration of peptides.

Ooi¹,

Oobatake²,

Némethy³

et al. 1987

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

731

603

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A method is described for the inclusion of the effects of hydration in empirical conformational energy computations on polypeptides. The free energy of hydration is composed of additive contributions of various functional groups. The hydration of each group is assumed to be proportional to the accessible surface area of the group. The constants of proportionality, representing the free energy of hydration per unit area of accessible surface, have been evaluated for seven classes of groups (occurring in peptides) by least-squares fitting to experimental free energies of solution of small monofunctional aliphatic and aromatic molecules. The same method has also been applied to the modeling of the enthalpy and heat capacity ofhydration, each of which is computed from the accessible surface area.The free energy of folding of a protein consists of the sum of contributions from the energy of its intramolecular interactions (1, 2) and from the free energy of interaction of the molecule with the surrounding solvent water. Exact computation of the latter contribution still poses problems (3). As a practical approach, hydration-shell models have been used. In these models, the free energy of interaction of water molecules with the solute is expressed in the form of an averaged effective potential of interaction of atoms (and functional groups) of a solute molecule with a layer of solvent around each atom (4-10)-i.e., in terms ofa potential ofmean force (3). An empirical free energy of hydration is assigned to every atom and group. When the conformation of the protein changes, some water is eliminated from the hydration shell whenever groups on the protein approach each other. The free energy change accompanying this process depends on the total free energy of hydration of the groups and on the amount of water being eliminated from the hydration shells. This amount, in turn, depends on the size and distance of separation of the groups that approach each other, and it can be computed by geometrical methods from the volumes of overlapping spheres (4-6, 10, 11).The hydration-shell model contains several approximations, which may be sources of error and also reduce the speed of computer-based numerical computations (8), such as the thickness of the shell, the apportioning of the free energy between overlapping hydration shells of covalently connected atoms, and the calculation of the volume of overlap of three or more hydration spheres that belong to nearby atoms. The latter problem can be overcome, however, by modifying the computing procedures (10, 11).We have initiated an alternative approach, in order to avoid these problems. We assume that the extent of interaction of any functional group i of a solute with the solvent is proportional to the solvent-accessible surface area Ai of group i (12-14) because the group can interact directly only with the water molecules that are in contact with the group at this surface. Thus, the total free energy of hydration of a solute molecule is given by Eq. 1: AGh = E Ai [1] where...

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“…It is interesting to note that the linear curves describing alkanes, alkenes, and alkadienes are each displaced by one carbon atom, which is equivalent to two hydrogen atoms (see Fig. 2 [5] The negative change in entropy is given by the temperature derivative of Eqs. 4 and 5 as AS" = -(AGOT*/T*) + AC0P In (T/T*) 20F [6] Fig.…”

mentioning

confidence: 99%

An equation of state describing hydrophobic interactions

Gill

Wadsö²

1976

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

176

101

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Several thermodynamic properties for the process of dissolution of pure hydrocarbons into water are found to be linearly related to the number of hydrogens on the hydrocarbon molecule. From the correlations found for the Gibbs energy change, enthalpy change, and heat capacity change, along with the use of an average minimum solubility temperature, an equation of state for the hydrophobic effect is derived. The entropy change upon dissolution per hydrocarbon hydrogen atom is close to -R In 2. A model based upon a "tetrahedrally" localized water molecule with one corner defined by a carbon-hydrogen group and the other three corners defined by water molecules is used to estimate the observed entropy and heat capacity changes.The availability of enthalpies of solution into water as a function of temperature for a set of hydrocarbons (1) has made possible the evaluation of corresponding entropies of solution from solubility measurement (2). In the course of correlating these results with structural features of the hydrocarbons studied, a significant descriptive parameter was found to be the number of hydrogens on the hydrocarbon species. A similar feature has also been implied in calculations for partial molar heat capacities of organic solutes in water. Linear correlations of the hydrophobic Gibbs energy and the molar volume (2) or surface area (3-5) of a given family of hydrocarbon groups have been obtained, but they do not provide detailed molecular insight into the nature of aqueous solutions of hydrocarbons.The enthalpies of solution of seven hydrocarbon liquids (benzene, toluene, ethyl benzene, propyl benzene, pentane, hexane, and cyclohexane) (1) are characterized by a positive linear dependence upon temperature and a temperature near room temperature where the enthalpy of solution is zero. It is convenient to describe the temperature dependence of the Gibbs energy change from this temperature of minimum solubility. This procedure enables the development of an empirical equation of state for hydrophobic interactions. At room temperature the enthalpy changes upon solution are small, and the dominant factor in the Gibbs energy of dissolution is the entropy change. The relation of these thermodynamic parameters to the number of hydrogen atoms in a hydrocarbon molecule leads to a particularly simple molecular picture of the nature of water molecules localized about each hydrocarbon hydrogen atom. It is hoped that this description will be useful in estimating thermodynamic properties of hydrophobic interactions in biological materials. Hydrophobic Gibbs energy change We define the hydrophobic Gibbs energy change AGO for the transfer process of taking hydrocarbon molecules from the pure hydrocarbon liquid phase to the standard state of the hydrocarbon in a dilute aqueous phase. In terms of chemical poten- [l]A correlationof the hydrophobic Gibbs energy change has been demonstrated with the carbon chain length for hydrocarbon families, such as normal saturated alkanes, and alkenes, as well as with aliphatic a...

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Solubility of nonelectrolytes in polar solvents. V. Estimation of the solubility of aliphatic monofunctional compounds in water using a molecular surface area approach

Cited by 152 publications

References 4 publications

Combined Simulation and Mutagenesis Analyses Reveal the Involvement of Key Residues for Peroxisome Proliferator-activated Receptorα Helix 12 Dynamic Behavior

Combined Simulation and Mutagenesis Analyses Reveal the Involvement of Key Residues for Peroxisome Proliferator-activated Receptorα Helix 12 Dynamic Behavior

Accessible surface areas as a measure of the thermodynamic parameters of hydration of peptides.

An equation of state describing hydrophobic interactions

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