Development of glycyl radical parameters for the OPLS-AA/L force field

On the basis of quantum chemical calculations C(alpha)-glycyl radical parameters have been developed for the OPLS-AA/L force field. The molecular mechanics hypersurface was fitted to the calculated quantum chemical surface by minimizing their molecular mechanics parameter dependent sum-of-squares deviations. To do this, a computer program in which the molecular mechanics energy derivatives with respect to the parameters were calculated analytically was developed, implementing the general method of Lifson and Warshel (J Chem Phys 1968, 49, 5116) for force field parameter optimization. This program, in principle, can determine the optimal parameter set in one calculation if enough representative value points on the quantum chemical potential energy surface are available and there is no linear dependency between the parameters. Some of the parameters in quantum calculations, including several new torsion types around a bond as well as angle parameters at a new central atom type, are not completely separable. Consequently, some restrictions and/or presumptions were necessary during parameter optimization. The relative OPLS-AA energies reproduced those calculated quantum chemically almost perfectly.     

Preferential solvation of indomethacin and naproxen in ethyl acetate + ethanol mixtures according to the IKBI method

The preferential solvation parameters of indomethacin and naproxen in ethyl acetate + ethanol mixtures are derived from their thermodynamic properties by using the inverse Kirkwood–Buff integrals method. It is found that both drugs are sensitive to solvation effects, so the preferential solvation parameter, δx_EA,D, is negative in ethanol-rich and ethyl acetate-rich mixtures but positive in compositions from 0.36 to 0.71 in mole fraction of ethyl acetate. It is conjecturable that in ethanol-rich mixtures, the acidic interaction of ethanol on basic sites of the analgesics plays a relevant role in the solvation. The more solvation by ethyl acetate in mixtures of similar co-solvent compositions could be due to polarity effects. Finally, the slight preference of these compounds for ethanol in ethyl acetate-rich mixtures could be explained as the common participation of basic sites in both solvents and the acidic site of ethanol. Nevertheless, the specific solute–solvent interactions remain unclear.     

Partial solubility parameters of lactose, mannitol and saccharose using the modified extended Hansen method and evaporation light scattering detection

The modified extended Hansen method was tested for the first time to determine partial solubility parameters of non-polymeric pharmaceutical excipients. The method was formerly tested with drug molecules, and is based upon a regression analysis of the logarithm of the mole fraction solubility of the solute against the partial solubility parameters of a series of solvents of different chemical classes. Two monosaccharides and one disaccharide (lactose monohydrate, saccharose and mannitol) were chosen. The solubility of these compounds was determined in a series of solvents ranging from nonpolar to polar and covering a wide range of the solubility parameter scale. Sugars do not absorb at the UV-vis region, and the saturated solutions were assayed with a recent chromatographic technique coupled to an evaporative light scattering detector. This technique was suitable to determine the concentration dissolved in most solvents. The modified extended Hansen method provided better results than the original approach. The best model was the four parameter equation, which includes the dispersion delta d, dipolar delta p, acidic delta a and basic delta b partial solubility parameters. The partial solubility parameters obtained, expressed as MPa1/2, were delta d = 17.6, delta p = 28.7, delta h = 19, delta a = 14.5, delta b = 12.4, delta T = 32.8 for lactose, delta d = 16.2, delta p = 24.5, delta h = 14.6, delta a = 8.7, delta b = 12.2, delta T = 32.8 for mannitol and delta d = 17.1, delta p = 18.5, delta h = 13, delta a = 11.3, delta b = 7.6, delta T = 28.4 for saccharose. The high total solubility parameters delta T obtained agree with the polar nature of the sugars. The dispersion parameters delta d are quite similar for the three sugars indicating that the polar delta p and hydrogen bonding parameters (delta h, delta a, delta b) are responsible for the variation in the total solubility parameters delta T obtained, as also found for drugs. The results suggest that the method could be extended to determine the partial solubility parameters of other non-polymeric pharmaceutical excipients.     

Prediction of internal standards in reversed-phase liquid chromatography: IV. Correlation and prediction of retention in reversed-phase ion-pair chromatography based on linear solvation energy relationships

This paper describes the results of the evaluation of a new solvation parameter model for reversed-phase ion-pair chromatography by linear gradient elution. This model is described as . The first six terms are the usual solvation parameter equation for neutral solutes, and the seventh term represents the contribution to retention from solute’s ionization. The last term describes the retention increase due to ion-pair effect. Retention times obtained for 60 solutes (neutral, acidic and basic) in acetonitrile/aqueous mobile phases with different ion-pair reagents (phosphoric acid, trifluoroacetic acid, heptafluorobutyric acid, perchloric acid, and hexafluorophosphoric acid) are used to evaluate the capability of the function. It is concluded that the model describes the retention of ionizable/ionized compounds under ion-pair conditions very well. Accordingly, the function extends the application of linear solvation energy relationships (LSERs) to ionizable compounds in ion-pair chromatography, and allows us to easily predict their retention for chromatographic optimization, including selectivity optimization and internal standard selection. Finally, the conclusion can be extended to ioscratic elution.     

Preferential Solvation of Some Sulfonamides in Propylene Glycol + Water Solvent Mixtures According to the IKBI and QLQC Methods

The preferential solvation parameters, which represent differences between the local and bulk mole fractions of the solvents near to the solute, in solutions of some sulfonamides in propylene glycol + water binary mixtures are derived from their thermodynamic properties by means of the inverse Kirkwood?Buff integrals (IKBI) and the Quasi-Lattice Quasi-Chemical (QLQC) method. From solvent effect studies, it is found that sulfonamides are sensitive to solvation effects; the preferential solvation parameter, δx _PG,S, is negative in water-rich mixtures but positive in compositions from 0.20 to 1.00 in mole fraction of propylene glycol according to IKBI method and positive in all co-solvent compositions if the QLQC method is considered. It is conjecturable that in water-rich mixtures, hydrophobic hydration around the aromatic ring and/or other non-polar groups plays a relevant role in the solvation. The greater solvation by propylene glycol mixtures of similar solvent compositions and in co-solvent-rich mixtures could be due mainly to polarity effects and acidic behavior of the sulfonamides, in contrast to the more basic solvent propylene glycol.     

Solvation parameters Part 1. Mutual improvements of several approaches and determination of two first sets of optimized values

An improvement in the characterization and the determination of the solvation parameters allows, not only a better knowledge of solutions, but also of some biological phenomena. In this paper, we test several published data and approaches in the field of solubility and solvation parameters in two ways: (i) the mutual independence of the parameters and (ii) their ability to take into account recently published gas-liquid chromatographic data. From this enquiry it arises that the most suitable published values are those of Abraham concerning 314 solutes. It also arises that the parameters of dispersion and orientation of this published data set are appreciably improved using two simple equations. In addition, a new set of optimized values for 133 solutes is given, by derivation from retention indices in gas-liquid chromatography (GLC) on five selected stationary phases, published by Kováts and co-workers and in the present study. The two sets have a total of 373 defined compounds.     

Principal component analysis of polarity and interaction parameters in inverse gas chromatography

Inverse gas chromatography is used in the characterization of aliphatic-aromatic and aromatic ketones, their oximes, and ketone-oxime or oxime-oxime mixtures. All these organic materials are used as liquid stationary phases in gas chromatographic columns. A series of polarity and Flory-Huggins interaction parameters are determined and used to describe the physicochemical properties of examined materials, metal extractants, and products of their degradation. Principal component analysis (PCA) is performed on a data matrix consisting of polarity and interaction parameters for ketones, their oximes, and mixtures. The calculations are carried out on the correlation matrix. It is found that seven principal components account for more than 95% of the total variance in the data, indicating that the polarity (interaction) parameters are not correlating well. Physical meanings are attributed to the principal components, the most influential ones being that the first and the second principal components account for several Flory-Huggins interaction parameters, whereas the fifth is correlated with criterion "A". The plots of component loadings show characteristic groupings of polarity indicators, whereas that of component scores show several groupings of stationary phases. Cluster analysis provides mainly the same groupings. PCA allows for the grouping of polarity and solubility parameters based on the information carried within those parameters. There is no need to use more than one parameter from each cluster. McReynolds polarity and the partial molar excess Gibbs free energy of solution per methylene group carry the same information. The groups of ketones, oximes, and their mixtures can be distinguished with the use of PCA on the basis of the measured polarity, solubility parameters, or both.     

Solvatochromic Linear Solvation Energy Relationships (LSER) for Solubility of Gases in Various Solvents by Target Factor Analysis

A linear solvation free energy relationship has been conducted to study the effects of solvent and solute properties on the free energy of solvation of inert gases and normal alkanes in different solvents. Factor analysis combined with target factor analysis was used to identify and quantify the factors controlling the variation of free energies of solvation, without the need to postulate any priori hypothetical method. Factor analysis of the solvation data revealed that there are two factors affecting the solubility of both types of gases in non‐polar as well as polar solvents. Target testing of the solvent parameters indicated that the Hildebrand solubility parameter of solvents is the major factor controlling the solubility of gases. Moreover, it was found that the coefficient of the Hildebrand solubility parameter in the linear solvation free energy equations has linear correlation with energy of vaporization and Lennard‐Jones force parameter of inert gases and number of carbon atoms and energy of vaporization of normal alkanes.     

Joint QSAR analysis using the Free-Wilson approach and quantum chemical parameters

A new quantitative structure-activity relationship (QSAR) technique combining the Free-Wilson method and constructed quantum chemical parameters was used to simulate the aqueous solubility (Sw), 1-octanol/water partition coefficient (Kow) of 14 new synthesized benzanilide derivatives and their 96 h acute toxicity (EC50) to Daphnia magna. The mode of action of the 14 selected compounds to Daphnia magna was shown to be a complex process involving a physical partition stage and a bio-chemical reaction stage. The results also indicated that the joint (QSAR) analysis was much effective than the original Free-Wilson method and Hansch method not only in predicting properties/toxicity, but also in investigating the mode of action of chemicals.     

Convex solubility parameters for polymers

Solubility parameters are certain measurable quantities that are observed to influence the ability of a solvent to fully dissolve a polymer. Current theory partitions the intermolecular forces between dispersion, polar, and hydrogen bonding interactions, thereby generating a three‐dimensional solubility parameter space. The Hansen solubility parameters of a polymer are taken to be the center of a sphere obtained from the best fit of the coordinates of good solvents in the parameter space. Investigations of several polymers (lignin, polyethersulfone, and bitumen) show that the convex hull of all known good solvents in the three‐dimensional parameter space also gives a meaningful interpretation of the solubility region. Several methods for computing the convex solubility parameters of a polymer from the convex solubility region are described. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2015 , 53, 1089–1097     

Making equation of state models predictive: Part 2: An improved PCP-SAFT equation of state

We use the PCP-SAFT equation of state, which is of the Van der Waals type and has a sound physical basis, to predict mixture properties, such as vapor–liquid and liquid–liquid equilibria, as well as excess enthalpies. We use molecular properties, such as dipole moment, quadrupole moment, polarizability and dispersion interaction coefficients, that have been determined quantum mechanically in Part I of this publication and adjust the remaining three pure compound parameters to pure compound data. We finally present a new combination rule for the dispersion energy parameter ? that is based on the quantum mechanically determined data. The predictions based on quantum mechanically determined pure compound properties along with the new combination rule show an improved performance compared to the original PCP-SAFT combination rule.     

Partial hessian fitting for determining force constant parameters in molecular mechanics

We present a new protocol for deriving force constant parameters that are used in molecular mechanics (MM) force fields to describe the bond‐stretching, angle‐bending, and dihedral terms. A 3 × 3 partial matrix is chosen from the MM Hessian matrix in Cartesian coordinates according to a simple rule and made as close as possible to the corresponding partial Hessian matrix computed using quantum mechanics (QM). This partial Hessian fitting (PHF) is done analytically and thus rapidly in a least‐squares sense, yielding force constant parameters as the output. We herein apply this approach to derive force constant parameters for the AMBER‐type energy expression. Test calculations on several different molecules show good performance of the PHF parameter sets in terms of how well they can reproduce QM‐calculated frequencies. When soft bonds are involved in the target molecule as in the case of secondary building units of metal‐organic frameworks, the MM‐optimized geometry sometimes deviates significantly from the QM‐optimized one. We show that this problem is rectified effectively by use of a simple procedure called Katachi that modifies the equilibrium bond distances and angles in bond‐stretching and angle‐bending terms. © 2016 Wiley Periodicals, Inc.     

Solvation model based on order parameters and a fast sampling method for the calculation of the solvation free energies of peptides

An analytical solvation model is proposed as a function of an order parameter, which represents the local arrangement of water molecules in the first solvation shell of peptide atoms. The model is combined with a fast sampling method, rotational isomeric state Monte Carlo, to sample efficiently the torsional degrees of freedom on a peptide backbone. This order parameter solvation model is shown to reproduce without ad hoc fitting parameters the solvation free energies of single amino acids and tripeptides with slightly better accuracy than the generalized Born model but with several orders of magnitude improvement in efficiency. This method is a potential candidate for efficiently and accurately tackling some important issues in biophysical chemistry that are related to solvation, for example, protein folding, ligand binding, etc. Our results also present fundamental new insights into solvation. Specifically, the local water geometry, represented in this work by a properly defined order parameter, carries the majority, if not all, of the energetic information of solvation, including solute-solvent interactions and solvent reorganization in the presence of the solute.     

Preferential solvation of methocarbamol in aqueous binary co-solvent mixtures at 298.15 K

The preferential solvation parameters of methocarbamol in dioxane + water, ethanol + water, methanol + water and propylene glycol + water mixtures are derived from their thermodynamic properties by using the inverse Kirkwood–Buff integrals (IKBI) method. This drug is sensitive to solvation effects, being the preferential solvation parameter δx_1,3, negative in water-rich and co-solvent-rich mixtures, but positive in mixtures with similar proportions of solvents, except in methanol + water mixtures, where positive values are found in all the methanol-rich mixtures. It is conjecturable that the hydrophobic hydration around the non-polar groups in water-rich mixtures plays a relevant role. Otherwise, in mixtures of similar solvent compositions, the drug is mainly solvated by co-solvent, probably due to the basic behaviour of the co-solvents; whereas, in co-solvent-rich mixtures, the preferential solvation by water could be due to the acidic behaviour of water. Nevertheless, the specific solute–solvent interactions present in the different binary systems remain unclear.     

A new quantum method for electrostatic solvation energy of protein

A new method that incorporates the conductorlike polarizable continuum model (CPCM) with the recently developed molecular fractionation with conjugate caps (MFCC) approach is developed for ab initio calculation of electrostatic solvation energy of protein. The application of the MFCC method makes it practical to apply CPCM to calculate electrostatic solvation energy of protein or other macromolecules in solution. In this MFCC-CPCM method, calculation of protein solvation is divided into calculations of individual solvation energies of fragments (residues) embedded in a common cavity defined with respect to the entire protein. Besides computational efficiency, the current approach also provides additional information about contribution to protein solvation from specific fragments. Numerical studies are carried out to calculate solvation energies for a variety of peptides including alpha helices and beta sheets. Excellent agreement between the MFCC-CPCM result and those from the standard full system CPCM calculation is obtained. Finally, the MFCC-CPCM calculation is applied to several real proteins and the results are compared to classical molecular mechanics Poisson-Boltzmann (MM/PB) and quantum Divid-and-Conque Poisson-Boltzmann (D&C-PB) calculations. Large wave function distortion energy (solute polarization energy) is obtained from the quantum calculation which is missing in the classical calculation. The present study demonstrates that the MFCC-CPCM method is readily applicable to studying solvation of proteins.     

Solvation parameters for amino acids

Atomic radii have been derived for the common amino acid side chains using a solvent interaction potential (SIP) based on quantum mechanically derived charges. Solvation energies calculated using these parameters are compared with those obtained using other sets of radii and charges, and from alternative methods. The differences from the experimental solvation energies for the nonionizable residues are all less than 10 kJ mol⁻¹. The largest error in the solvation energy occurs for acetic acid (−16.0 kJ mol⁻¹). For the charged side chain systems the difference from experiment are all less than 10 kJ mol⁻¹. SIP parameters for the aminoacetaldehyde derivatives of the common amino acids are presented. These are used in the calculation of the relative binding energies of six benzamidine inhibitors with trypsin. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 428–442, 1999