Improved electrostatic properties using combined Mulliken and hybridization-displaced charges for radicals

Effects of explicit consideration of charges displaced from atomic sites due to atomic orbital hybridization called hybridization-displaced charges (HDC) on dipole moments and surface molecular electrostatic potentials of certain radicals and their complexes with closed-shell molecules have been studied. HDC were computed for several radicals and their complexes at the B3LYP/6–31G** level of theory. At this level, HDC consist of three point charges associated with hydrogen atoms and seven point charges associated with heavy atoms belonging to the second row of the periodic table. HDC are so calculated that the contribution of each atom to the component of molecular dipole moment arising due to atomic orbital hybridization is preserved. It is found that dipole moments and electrostatic potentials of the systems studied here can be obtained with a significantly improved accuracy using a combination of Mulliken charges and HDC over that obtained by Mulliken charges only. Figure Surface MEP map of H₂O-HO· radical complex obtained using Mulliken charges combined with HDC     

Beyond CHELP: improved potential derived charges for sugars

The partitioning of the overall molecular charge distribution into atom centered monopole charges, while quantum mechanically ill-defined, is nevertheless a technique which finds applications in several broad classes of chemical problems. Charges derived from fits to electrostatic potentials have an intuitive appeal since, in principle, these could be derived from either theoretical or experimental data. It has been noted, however, that such potential derived charges can be conformationally dependent in ways that do not appear to reflect the changes in the molecular wavefunction. Both the algorithm used for selecting points at which the molecular electrostatic potential will be fit and the density of points used in the fit have been suggested to influence the resultant charges. Recently [Stouch TR, Williams DE (1992) J Comp Chem 13: 622–32; Stouch TR, Williams DE (1993) J Comp Chem 14: 858–66] it has been noted that numerical difficulties may make it impossible to fit all the atomic charges in a molecule. Singular value decomposition (SVD) of the linear least squares matrices used in fitting atom based monopoles to molecular electrostatic potentials provides a tool for evaluating the integrity of the calculated charges. Based on the SVD analysis for a selected group of molecules we have noted particularly that increasing the molecular size reduces the fraction of charges which can be validly assigned. Users of PD derived charges, especially those who are using those charges for tasks other than reproduction of the MEP, should be aware that there is a high probability that a significant portion of those charges are statistically unreliable. Therefore, charges in many biological molecules, such as sugars, prove to be difficult to obtain by potential derived (PD) methods such as CHELP or CHELPG. Results from the SVD can be used to both assess PD charges and to generate an improved, albeit incomplete, set. Improved PD fits are presented for a series of simple saccharides. Abbreviations: HF, Hartree-Fock; LLS, linear least squares; MEP, molecular electrostatic potential; PD, potential derived; SVD, singular value decomposition This revised version was published online in November 2006 with corrections to the Cover Date.     

A Detailed Study of VESPA Electrostatic Potential-Derived Atomic Charges

VESPA, an improved semiempirical method for the calculation of electrostatic potential-derived atomic charges has been tested. It is shown that this approach is even less dependent upon molecular orientation than "high density" CHELPG ab initio ESP-derived charges. The conformational dependence of VESPA charges has been investigated for rotation around the C-N bond in formamide and 11 different conformers of glycerolphosphorylcholine. The results obtained are also compared to the corresponding ab initio values. Finally, VESPA is used to calculate electrostatic potential-derived charges for bioorganic molecules. We discuss the abilities and the limitations of ESP charges in this area.     

A Composite Polyelectrolytic Matrix for Controlled Oral Drug Delivery

The purpose of this study was to formulate drug-loaded polyelectrolyte matrices constituting blends of pectin, chitosan (CHT) and hydrolyzed polyacrylamide (HPAAm) for controlling the premature solvation of the polymers and modulating drug release. The model drug employed was the highly water-soluble antihistamine, diphenhydramine HCl (DPH). Polyelectrolyte complex formation was validated by infrared spectroscopy. Matrices were characterized by textural profiling, porositometry and SEM. Drug release studies were performed under simulated gastrointestinal conditions using USP apparatus 3. FTIR spectra revealed distinctive peaks indicating the presence of –COO⁻ symmetrical stretching (1,425–1,390 cm⁻¹) and -NH₃⁺ deformation (1,535 cm⁻¹) with evidence of electrostatic interaction between the cationic CHT and anionic HPAAm corroborated by molecular mechanics simulations of the complexes. Pectin–HPAAm matrices showed electrostatic attraction due to residual –NH₂ and –COO⁻ groups of HPAAm and pectin, respectively. Textural profiling demonstrated that CHT-HPAAm matrices were most resilient at 6.1% and pectin–CHT–HPAAm matrices were the least (3.9%). Matrix hardness and deformation energy followed similar behavior. Pectin–CHT–HPAAm and CHT–HPAAm matrices produced type IV isotherms with H3 hysteresis and mesopores (22.46 nm) while pectin–HPAAm matrices were atypical with hysteresis at a low P/P₀ and pore sizes of 5.15 nm and a large surface area. At t _2 h, no DPH was released from CHT–HPAAm matrices, whereas 28.2% and 82.2% was released from pectin–HPAAm and pectin–CHT–HPAAm matrices, respectively. At t _4 h, complete DPH release was achieved from pectin–CHT–HPAAm matrices in contrast to only 35% from CHT–HPAAm matrices. This revealed the release-modulating capability of each matrix signifying their applicability in controlled oral drug delivery applications.     

Effects of Thermal Curing Conditions on Drug Release from Polyvinyl Acetate–Polyvinyl Pyrrolidone Matrices

This study aimed to investigate the effects of dry and humid heat curing on the physical and drug release properties of polyvinyl acetate–polyvinyl pyrrolidone matrices. Both conditions resulted in increased tablet hardness; tablets stored under humid conditions showed high plasticity and deformed during hardness testing. Release from the matrices was dependent on the filler's type and level. Release profiles showed significant changes, as a result of exposure to thermal stress, none of the fillers used stabilized matrices against these changes. Density of neat polymeric compacts increased upon exposure to heat; the effect of humid heat was more evident than dry heat. Thermograms of samples cured under dry heat did not show changes, while those of samples stored under high humidity showed significant enlargement of the dehydration endotherm masking the glass transition of polyvinyl acetate. The change of the physical and release properties of matrices could be explained by the hygroscopic nature of polyvinyl pyrrolidone causing water uptake; absorbed water then acts as a plasticizer of polyvinyl acetate promoting plastic flow, deformation, and coalescence of particles, and altering the matrices internal structure. Results suggest that humid heat is more effective as a curing environment than dry heat for polyvinyl acetate–polyvinyl pyrrolidone matrices.     

Effect of a Pharmaceutical Cationic Exchange Resin on the Properties of Controlled Release Diphenhydramine Hydrochloride Matrices Using Methocel K4M or Ethocel 7cP as Matrix Formers

This work was aimed at evaluating the effect of a pharmaceutical cationic exchange resin (Amberlite IRP-69) on the properties of controlled release matrices using Methocel K4M (HPMC) or Ethocel 7cP (EC) as matrix formers. Diphenhydramine hydrochloride (DPH), which was cationic and water soluble, was chosen as a model drug. HPMC- and EC-based matrices with varying amounts (0–40%w/w) of resin incorporation were prepared by a direct compression. Matrix properties including diameter, thickness, hardness, friability, surface morphology and drug release were evaluated. The obtained matrices were comparable in diameter and thickness regardless of the amount of resin incorporation. Increasing the incorporated resin decreased the hardness of HPMC- and EC-based matrices, correlating with the degree of rupturing on the matrix surfaces. The friability of HPMC-based matrices increased with increasing the incorporated resin, corresponding to their decreased hardness. In contrast, the EC-based matrices showed no significant change in friability in spite of decreasing hardness. The incorporated resin differently influenced DPH release from HPMC- and EC-based matrices in deionized water. The resin further retarded DPH release from HPMC-based matrices due to the gelling property of HPMC and the ion exchange property of the resin. In contrast, the release from EC-based matrices initially increased because of the disintegrating property of the resin, but thereafter declined due to the complex formation between released drug and dispersed resin via the ion exchange process. The release in ionic solutions was also described. In conclusion, the incorporated resin could alter the release and physical properties of matrices.     

Theoretical and experimental studies of vibrational spectra and thermal analysis of 2-nitroaniline and its cation

The FTIR spectrum of 2-nitroaniline was recorded in the regions 4000–400 cm⁻¹. The optimized molecular geometry, bond orders, atomic charges, harmonic vibrational wave numbers and intensities of vibrational bands of 2-nitroaniline and its cation were calculated at DFT levels invoking two different basis sets 6-31G** and 6-31+G** using Gaussian 03W program. The X-ray geometry and FTIR vibrational frequencies were compared with the results of DFT calculations. The thermal stability of 2NA is studied by the thermo gravimetric analysis (TGA). Experimental degradation process of 2-nitroaniline was interpreted with the bond order analysis. The Mulliken atomic charge analysis was also made in the present study. Based on the molecular geometry and Mulliken charge analysis, intra molecular hydrogen bonding was identified.     

Benchmark of different charges for prediction of the partitioning coefficient through the hydrophilic/lipophilic index

A few different theoretical methods for assigning the partial atomic charges were benchmarked for calculation of the hydrophilic/lipophilic index (HLI). The coefficients were selected to produce the best correlation of the HLI values with the experimental octanol-water partition. Different parameters were checked in calculations of partial charges to get the best performance of the HLI values obtained. Thus, four partitioning schemes (Coulson, Mulliken, Merz-Kollman, Ford-Wang) were benchmarked for calculations of atomic charges with six semiempirical methods (AM1, PM3, RM1, PM6, PM6-D3H4, PM7). Moreover, five distinct types of partial atomic charges (Mulliken, Hirshfeld, Löwdin, CHELPG, NPA), obtained at the Hartree–Fock and DFT levels of theory with three basis sets, were tested for their ability to produce the HLI values with the best correlation to experimental logP coefficients of 50 mono-charged organic anions. In the case of the semiempirical methods, the best correlation between the HLI and logP values (the correlation coefficient r?=?0.9216) was obtained with the AM1 Ford–Wang parametric electrostatic potential charges. The Mulliken and Coulson charges calculated with the PM7 method can be used as an alternative to AM1, with the r values of 0.9107 and 0.8984, respectively. In the case of the DFT, the PBE/def2-TZVP natural population analysis charges produce the best correlation (r?=?0.9220). Nevertheless, in spite of a marginally lower performance (r?=?0.9159), the NPA charges computed at the PBE/def2-SVP level are more robust and can be regarded as the optimum choice for calculating the HLI values.

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Graphical abstract The hydrophilic/lipophilic index (HLI)

     

Hybridization-displaced charges for amino-acids: a new model using two point charges per atom along with bond-center charges

A new charge distribution is proposed for the amino acids where each atom is associated with two point charges while each bond center is associated with one point charge. Centroids of charges arising due to atomic orbital hybridization called hybridization-displaced charges (HDC) and those located at the atomic sites and bond centers obtained by a modified form of the Mulliken scheme were combined. The density matrix calculations required for this analysis were performed at the B3LYP/6-31G** level of density functional theory. The combination of HDC centroids with the modified Mulliken charges was found to yield dipole moments and surface molecular electrostatic potentials (MEP) of the amino acids in good agreement with those obtained by rigorous DFT calculations or those obtained using the MEP-fitted CHelpG charges. This study shows that the combination of HDC centroids with the modified Mulliken charges is significantly superior to the conventional Mulliken charges.     

A force field for naproxen

A united-atom potential model for naproxen suitable for molecular dynamics (MD) simulation has been developed. The charge distribution is approximated by point charges obtained from ab initio calculations using the CHELPG method. Also the intramolecular interactions such as bond and angle vibration, and the torsion potential are obtained from ab initio calculations. The dispersive interaction contribution is taken from the literature. By MD simulation using a naproxen film in slap geometry, the temperature dependence of the density, surface tension and self-diffusion coefficient as well as the melting temperature for the developed potential model are obtained.     

Monte Carlo Study of Structural and Thermodynamic Properties of Liquid Chloroform Using a Five Site Model

A five site potential model combining Lennard–Jones plus Coulomb potential functions has been developed for chloroform molecule. The partial charges needed for Coulombic interactions were derived using the chelpg procedure implemented in the gaussian 92 program. These calculations were performed at the MP2 level with MC-311G* basis set for Cl and 6-311G** for C and H atoms. The parameters for the Lennard–Jones potentials were optimized to reproduce experimental values for the density and enthalpy of vaporization of the pure liquid at 298 K and 1 atm. The statistical mechanics calculations were performed with the Monte Carlo method in the isothermic and isobaric (NpT) ensemble. Besides the values obtained for density, ρ, and molar enthalpy of vaporization at constant pressure, Δ H_V, for liquid chloroform, results for molar volume, V_m, molar heat capacity, C_p, isobaric thermal expansivity, α_p, and isothermal compressibility, κ_T, for this pure liquid are also in very good agreement with experimental observations. Size effects on the values of thermodynamic properties were investigated. The potential model was also tested by computing the free energy for solvating one chloroform molecule into its own liquid at 298 K using a statistical perturbation approach. The result obtained compares well with the experimental value. Site–site pair correlation functions were calculated and are in good accordance with theoretical results available in the literature. Dipole–dipole correlation functions for the present five site model were also calculated at different carbon–carbon distances. These correlations were compared to those obtained using the four site model reported in the literature. An investigation of the solvent dependence of the relative free energy for cis/trans conversion of a hypothetical solute in TIP4P water and chloroform was accomplished. The results show strong interaction of water and chloroform molecules with the gauche conformer. The value obtained for the free energy barrier for cis/trans rotation in TIP4P water is higher than that for chloroform. This result is in agreement with the continuous theory for solvation as the conformer with higher dipole moment is more favoured by the solvent with higher dieletric constant. The results also show an increase in entropy as the solute goes from the cis to the trans geometry and this result is more appreciable in the aqueous solution. This revised version was published online in June 2006 with corrections to the Cover Date.     

Detection of aromatic catabolic gene expression in heterogeneous organic matter used for reduction of volatile organic compounds (VOC) by biofiltration

A qualitative procedure of purified DNA/RNA co-extraction from complex organic matter, used as biofilter support for removing volatile organic compounds, was set up and applied to detect xylene monooxygenase gene expression by RT-PCR. A DNA/RNA extraction protocol based on a combination of sample lyophilization pre-treatment and CTAB––phenol/chloroform extraction procedure was optimized for the recovery of purified nucleic acids [100–500 ng DNA (10 kb) and 0.5–2 μg of rRNA 16S from 100 mg matrix]. PCR and RT-PCR protocols were established to detect xylene monooxygenase gene expression starting from differentially induced organic matrices obtained by biofiltration technology. This work allowed the microbial degradation activities in heterogeneous organic solid media to be studied and suggests a rapid method to follow specific biological activities during solid and/or semisolid organic substrates biotransformation.     

Alterations of calf venous and arterial compliance following acclimation to heat administered at a fixed daily time in humans

We investigated the effects of heat acclimation on venous and arterial compliance in humans. Four male and four female volunteers were exposed to an ambient temperature of 40°C and relative humidity of 40% for 4 h (1330–1730 hours) per day for 9–10 consecutive days. The calf venous compliance (CV) was estimated using venous occlusion plethysmography with a mercury-in-silastic strain gauge placed around the right calf at its maximum girth. The compliance of the small (CSA) and large (CLA) arteries were assessed by reflective and capacitance compliance by analyzing the radial artery blood pressure waveforms, basing on the use of a modified Windkessel model. The calf CV, CSA, CLA, systolic and diastolic blood pressures, heart rate and core temperature were determined twice a day, 0930–1100 hours (AM test) and 1500–1630 hours (PM test), in both heat-acclimated and non-heat-acclimated (control) conditions. Heat acclimation appeared to decrease blood pressures, heart rate and significantly lowered core temperature only in the PM test. In the control condition, the calf CV was not affected by the time of day and the CSA was significantly depressed in the PM test. After acclimation to heat, the calf CV significantly increased and the CSA did not decrease in the PM test. The results presented suggest that repeated heat exposure in humans, for 4 h at a fixed time daily, increases the calf CV and the CSA particularly during the period when the subjects were previously exposed to heat.     

Calculations of the charge distribution in dodecyltrimethylammonium: a quantum chemical investigation

In this work we report the atomic partial charges evaluated on dodecyltrimethylammonium ion. The values obtained from 17 quantum methods [CHELP, CHELPG, MK, NPA at (HF, LDA, PBE, B3LYP)//6-31G++(d,p) level and APT at B3LYP//6-31G++(d,p)] on the molecule optimised at B3LYP/6-31G++(d,p) level were compared to two semiempirical methods (Gasteiger and Qeq) and the commercial force field PCFF. All methods based on quantum calculation gave a positive charge delocalised on at least the first four alkyl groups of the tail. However, those deriving partial charges from the electrostatic potential gave an unrealistic set of alternative positive and negative alkyl group charges along the tail. In comparison, the NPA and APT methods lead to a steady decrease in the partial charges from the third alkyl group, and agreed closely with the representation of the electrostatic potential mapped onto the 0.002 au isodensity surface. The choice of the exchange correlation treatment does not drastically influence the atomic partial charges.     

The application of databases and PCR in the cloning of glycosidase genes from the protozoan Tritrichomonas foetus

Conserved sequence amplification (CSA) has been used to obtain sequence data for two glycosidase genes from the primitive eukaryote Tritrichomonas foetus. Few genes have been cloned from this organism, and there is little information concerning protein sequence. CSA is reliant on the use of database searches to identify short sequences of 3–9 amino acids conserved within a protein across a wide range of species. PCR primers are then constructed based on this sequence data and the DNA is amplified and sequenced. In the case of the β-galactosidase gene, N-terminal amino acid sequence data were used to construct a primer that replaced the upstream primer to ensure the amplified product was related to β-d galactosidase CSA was also applied to the gene encoding the enzyme β-N-acetyl-d-glucosaminidase from T. foetus, but in this case a segment of DNA was amplified, which, if correct, should contain a third conserved motif. The products of the CSA were sequenced, and the data obtained were compared to data in the SwissProt database. The results obtained suggest that this approach is useful for the cloning of genes to obtain novel sequence data from organisms where little genetic information is available.     

Optimized intermolecular potential for nitriles based on Anisotropic United Atoms model

An extension of the anisotropic united atoms intermolecular potential model is proposed for nitriles. The electrostatic part of the intermolecular potential is calculated using atomic charges obtained by a simple Mulliken population analysis. The repulsion-dispersion interaction parameters for methyl and methylene groups are taken from transferable AUA4 literature parameters [Ungerer et al., J. Chem. Phys., 2000, 112, 5499]. Non-bonding Lennard-Jones intermolecular potential parameters are regressed for the carbon and nitrogen atoms of the nitrile group (–C≡N) from experimental vapor-liquid equilibrium data of acetonitrile. Gibbs Ensemble Monte Carlo simulations and experimental data agreement is very good for acetonitrile, and better than previous molecular potential proposed by Hloucha et al. [J. Chem. Phys., 2000, 113, 5401]. The transferability of the resulting potential is then successfully tested, without any further readjustment, to predict vapor-liquid phase equilibrium of propionitrile and n-butyronitrile. Figure Saturated vapour pressure of nitriles calculated in this work by molecular simulation compared to experimental data: a) for acetonitrile and b) for both propionitrile and butyronitrile