Nonpolar surface area

As the logarithm of 1-octanol-water partition coefficient (log P) describes the hydrophobicity of molecules and the retention of solutes in RP-HPLC depends on the hydrophobicity, a strong correlation can be expected between the log V value and the retention of solutes in RP-HPLC. Besides log P, a considerable number of physicochemical parameters have been tested for their capacity to predict retention in RP-HPLC. Thus, Snyder s polarity index, fraction of positively and negatively charged surface area, molecular bulkiness, nonpolar surface area, electron donor and acceptor capacity, various ster-ical parameters, and the energy of highest occupied molecular orbit have all been included in QSRR calculations. 

Livingstone, J.R., R.S. Spolar, and M.T. Record, Jr. 1991. Contribution to the thermodynamics of protein folding from the reduction in water-accessible nonpolar surface area. Biochemistry 30 4237 1244. 

Hydrophohicity-related the logarithm of the octanol-water partition coefficient, LogP [30], included in GlogP [31] and ELogP [24] the logarithm of the (molar) aqueous solubility [32, 33], included in ELogSw [25] the nonpolar surface area, both in Pf (NPSA) and normalized to the total surface area (%NPSA) ... 

To help clarify the nature of the site we have determined systematically its affinity for many different structurally related compounds. Thus, in the case of simple aliphatic carboxylate ions, affinities vary in proportion to their nonpolar surface areas as shown in Figure 14 (29,47). The straight line is drawn for the unbranched carboxylates, butyrate through... 

Figure 14. Free energy of binding vs. nonpolar surface areas for a series of aliphatic carboxylate ions interacting with HSA.

Dissociation constants were determined from their inhibition of the reaction between HSA and p-nitrophenyl acetate as determined in pH 7.4, 0.03M triethanolamine / HCl at 25° C. Nonpolar surface areas were calculated according to Hermann (48/ The carboxylate ions are as follows (1) butyrate (2) valerate (3) hexanoate (4) heptanoate (5) octanoate (6) nonanoate (7) decanoate (8) undecanoate (9) dodecanoate (10) cyclohexanecarboxylate (11) 1-methyl-1-cyclohexanecarboxylate (12) cyclohexylacetate (13) 2-n-propylvalerate and... 

The theory also predicts that the retention of a protein will be related to the nonpolar surface area of the sample. This prediction is supported by the observed retention time for the apolipoproteins C-I, C-II, and C-III on an alkylphenyl column in the presence of an acetonitrile gradient (Fig. 4). The observed elution order is consistent with the known polarity of these proteins, with the apolipoprotein of the greatest nonpolar surface areas being retained the longest (/J). The isomers of the apolipoprotein C-III differ in the sialic acid content (0-2 residues) of the carbohydrate chain attached to Thrj4. One would expect that the polar sialic acid residue would decrease the nonpolar surface area of the protein molecule. The observed elution order of these isomers (Fig. 4) can be seen to be consistent with the sialic acid content. 

In an attempt to rationalize the large variety of buffers used to date in protein HPLC separations, it is necessary to briefly return to the separation mechanism based on the hydrophobic effect. This mechanism related the retention of a sample on a reversed-phase column to the nonpolar surface area of a sample molecule. A possible explanation of the dramatic effect of ion-pairing reagents on the retention of proteins on reversed-phase columns can then be based on the modification of surface polarity of the protein molecule on association with suitable counterions. In the absence of salts dissolved in the mobile phase, the peptide or protein sample probably has some counterions associated with the sample. Alternatively, the basic side chains of the protein may be neutralized by a salt bridge with an acidic residue which is adjacent in the three-dimensional structure. In either case, the contribution of the ammonium group to the surface polarity is relatively small. Figure 13 shows the result of association of the amine cation with a highly polar anion such as phosphate, which has a substantial sphere of hydration. In this case, the nonpolar area of the... 

This pictorial representation of a possible mechanism of action of a polar ion-pairing reagent has allowed prediction of what anions will be useful in decreasing the retention of a given protein. Alternatively, a nonpolar anion such as hexane sulfonate could be expected to associate with an ammonium ion present in the sample, with an increase in the nonpolar surface area and hence retention time. For example, apolipopro-tein C-III, which is readily eluted by an organic solvent gradient from a Cig column in the presence of phosphate anions, is retained indefinitely if butanesulfonate is used as the counterion. 

To determine whether pharmacological differences are dictated by differences in nonpolar accessible surfaces of the targets within ligand-binding sites, a nonpolar distance, dnp (i,j), between the affinity-assayed kinases i, j is introduced. The dnp (i,j) is determined by differences in accessible nonpolar surface areas of the respective nonpolar hulls, Hnp ( ), Hnp (j). As rigorously defined in the previous... 

Geometrical 3D structure of molecule (molecular volume, solvent accessible surface area, polar and nonpolar surface area)... 

It is shown 30) that the analysis of a relationship between the salting-out constants of a given protein and the molal surface tension increments makes it possible to estimate the relative surface hydrophobicity which is calculated as the ratio of the nonpolar surface area to the molecular weight of the protein. According to the concept developed by Melander et al 30), the hydrophobic character of a protein is believed to be constant at both high and physiological concentrations of different inorganic salts, which seems to be untrue in most cases (see below). 

The primary contribution to the hydrophobic effect comes from the favorable increase in system entropy upon the release of ordered first-shell waters from nonpolar surface areas on both the macromolecule and the ligand upon ligand binding there are also secondary enthalpic contributions. 

The hydrophobic effect contributes between 25 to 50 cal/mol. A2 of nonpolar surface area that is freed from water. 

The relationship between individual components appears to indicate that the first and second SaSA dimensions can be related to the first and third ALMOND dimensions, with an emphasis on the first component. The first SaSA component is dominated by size-related descriptors, e.g., the total number of heavy atoms, MW, CMR, and polarizability. These properties explain approximately 60% of the first ALMOND component, suggesting that large internode distances and high internode interaction energies dominate this component. The third ALMOND component has a weaker relationship (25%) to hydrophobicity descriptors such as CLOGP, ELogP, nonpolar surface area, and the number of nonpolar atoms [123]. Only the fourth ALMOND component appears to be related (under 25%) with hydrogen-bond-related, e.g., HYBOT descriptors, whereas the second, fifth, and sixth ALMOND... 

The introduction of more complex datasets used for model development has pointed at the need for several descriptors and multivariate data analysis (Table 16-3). For instance, combinations of PSA and nonpolar surface area (NPSA) proved to predict the permeability of a series of peptides when PSA alone failed [41], Moreover, the introduction oflarger structures and structures with larger flexibility showed that the partitioned total surface areas (PTSAs), that is, the surface area of the molecule occupied by a specific atom, and/or descriptors related to the flexibility of the molecule are in the permeability predictions [42, 43],... 

When a nonpolar molecule is surrounded by water, stronger than normal water-water interactions are formed around the solute molecule to compensate for the weaker interactions between solute and water. This results in an increasingly ordered arrangement of water molecules around the solute and thus a negative entropy of dissolution. The decrease in entropy is roughly proportional to the nonpolar surface area of the molecule. The association of two such nonpolar molecules in water reduces the total nonpolar surface area exposed to the solvent, thus reducing the amount of structured water, and therefore providing a favourable entropy of association. 

Particularly relevant to the gas-partiele partitioning of SVOCs is the carbonaceous fraction of the partieles, ineluding organic matter (OM) as well as the elemental carbon (black carbon or soot). The weight fraction of OM, fau, is an important independent variable in the prediction of Kp for SVOCs. Soot particles are highly porous with large nonpolar surface areas, which render them high affinity for SVOCs, particularly those with planar molecular structures such as PAHs. 

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