Conformational and structural stability of the single molecule and hydrogen bonded clusters of para aminobenzoic acid in the gas and solution phases

The crystallographic structures of the α- and β- polymorphic forms of para aminobenzoic acid are deconstructed into their constituent hydrogen bonding molecular structural building blocks of monomers, dimers, tetramers and octamers, where they are analysed using ab initio quantum mechanical calculations of their conformation and cluster stability in solution. The molecular conformation found in the β-form is less stable than the same found in the α-form for both the gas and solution phases, suggesting that this causes a slight increase in the barrier to the crystallisation of the β-form in comparison to the α-form. The solution populations of the self-associated OH⋯O H-bonding ‘classic carboxylic acid dimer’, present in the α- and not the β-structure, is calculated to dominate in acetonitrile, dimethyl sulfoxide, ethanol, ethyl acetate, methanol, nitromethane and water. It is observed that this classic dimer is least stable in water, compared to the other PABA crystallisation solvents, with the OH⋯N H-bonding interaction present in the β-form being the second most stable dimeric interaction. These results are discussed in terms of the crystallisability and polymorphic behaviour of the α and β forms of PABA from the afore mentioned crystallisation solvents, whilst detailing how this approach could be reproducible for a range of polymorphic crystalline materials

Peptide Bond Distortions from Planarity: New Insights from Quantum Mechanical Calculations and Peptide/Protein Crystal Structures

By combining quantum-mechanical analysis and statistical survey of peptide/protein structure databases we here report a thorough investigation of the conformational dependence of the geometry of peptide bond, the basic element of protein structures. Different peptide model systems have been studied by an integrated quantum mechanical approach, employing DFT, MP2 and CCSD(T) calculations, both in aqueous solution and in the gas phase. Also in absence of inter-residue interactions, small distortions from the planarity are more a rule than an exception, and they are mainly determined by the backbone ψ dihedral angle. These indications are fully corroborated by a statistical survey of accurate protein/peptide structures. Orbital analysis shows that orbital interactions between the σ system of Cα substituents and the π system of the amide bond are crucial for the modulation of peptide bond distortions. Our study thus indicates that, although long-range inter-molecular interactions can obviously affect the peptide planarity, their influence is statistically averaged. Therefore, the variability of peptide bond geometry in proteins is remarkably reproduced by extremely simplified systems since local factors are the main driving force of these observed trends. The implications of the present findings for protein structure determination, validation and prediction are also discussed

Revealing the Roles of Desolvation and Molecular Self-Assembly in Crystal Nucleation from Solution: Benzoic and p -Aminobenzoic Acids

There has been much recent interest in the role of solution chemistry and in particular the importance of molecular self-assembly in the nucleation of crystalline phases. Techniques such as FTIR and NMR have highlighted the existence of solution-phase dimers which in many cases mirror the structural synthons found in the resulting macroscopic crystals. However, there are no reported examples in which this new insight into the solution phase has been linked directly to the kinetics of crystal nucleation. Here for the first time, using a combination of solution FTIR, computational chemistry, and measured crystal nucleation rate data, such a link is demonstrated for p-aminobenzoic (PABA) and benzoic acids nucleating from polar and nonpolar solvents. Solute dimerization and desolvation are found to be rate-determining processes in the overall nucleation pathway

Towards an understanding of the nucleation of alpha-para amino benzoic acid from ethanolic solutions: A multi-scale approach

The molecular assembly and subsequent nucleation of para-amino benzoic acid (PABA) from ethanolic solutions is probed using a multi-scale and multi-technique approach. This is applied by examining and interrelating information regarding the molecular, solution-state, cluster, solid-state and surface structures to understand why the alpha form of PABA is crystallised in preference to its low temperature beta form. Calculations suggest that conformational changes within the solute molecule play little or no role in directing the nucleation of either the alpha or beta crystal forms. Combined ab initio and molecular dynamics calculations of the stability of small clusters in solution suggests that the hydrogen-bonded carboxylic acid dimers, present in the alpha structure, are the most stable in solution and play a major role in the self-assembly and polymorphic expression of the alpha form in ethanol in preference to the beta form. These calculations are in good agreement with X-ray small-angle scattering analysis which reveals the presence of PABA clusters in ethanol which are consistent with the size and shape of a carboxylic acid dimer. SAXS studies also reveal the presence of larger cluster structures in a size range 10-40 nm which appear to grow, perhaps reflecting a change in the balance between monomers and dimers within the solution during the nucleation process. The results of crystallisation-kinetics experiments indicate an instantaneous nucleation mechanism where the number of instantaneously nucleated crystallites is calculated to be 1360-660 nuclei per ml and the subsequent growth is found to be only rate limited by diffusion of the growth unit to the crystallite surface. A linear dependence of growth rate with respect to supersaturation is observed for the (0 1 -1) capping face, which is associated with strong π-π stacking interactions. This is consistent with a solid-on-solid mechanism associated with surface roughened growth and concomitant poor lattice-perfection. Conversely, the side (1 0 -1) surface has a growth mechanism consistent with a 2D nucleation birth and spread mechanism. Hence, these mechanisms result in very fast growth along the b-axis and the needle-like morphology that is observed for alpha-PABA

Seasonal variations of trihalomethanes (THMs) in water distribution networks of Istanbul City

Seasonal variations of trihalomethane (THM) concentrations were investigated within distribution systems of the Buyukcekmece water treatment plant in Istanbul City (Turkey). The investigation was based on an intensive 30-week sampling program, undertaken during the spring, summer and fall of the year 2003. THMs and other water quality and operational parameters were monitored at points along the distribution system between the treatment plant and the system's extremity. The results showed that THM concentrations vary significantly between finished waters and water at the distribution network. When water temperature exceeds 24 degrees C in summer, the THM levels are 1.2-1.8 times higher than finished water, while when water temperature is below 15 degrees C in the spring and fall, the measured THM concentrations at the system's extremity were very rarely higher than 100 mu g/L. Finally, THM levels were measured at sampling points representing progressively greater travel times from the plant to the extremity of the distribution system. Multiple regression analysis was also conducted in order to estimate THMs from total organic carbon, temperature, and chlorine dose parameters. The regression model resulted in a R-2 value of 0.827

A computational study of Anthracyclines interacting with lipid bilayers: Correlation of membrane insertion rates, orientation effects and localisation with cytotoxicity

Anthracyclines interact with DNA and topoisomerase II as well as with cell membranes, and it is these latter interactions that can cause an increase in their cytotoxic activity. In the present study a detailed computational analysis of the initial insertion, orientation and nature of the interaction occurring between Anthracyclines and two different lipid bilayers (unsaturated POPC and saturated DMPC) is explored through molecular dynamics (MD) simulations; four Anthracyclines: Doxorubicin (DOX), Epirubicin (EPI), Idarubicin (IDA) and Daunorubicin (DAU) were examined. The results indicate that the increased cytotoxicity of DOX, in comparison to the other three analogues, is correlated with its ability to diffuse at a faster rate into the bilayers. Additionally, DOX exhibited considerably different orientational behaviour once incorporated into the bilayer and exhibited a higher propensity to interact with the hydrocarbon tails in both lipids indicating a higher probability of transport to the other leaflet of the bilayer

Differential UV Spectroscopy Approach

In this study, the changes in UV absorbance of water samples were characterized using defined differential UV spectroscopy (DUV), a novel spectroscopic technique. Chlorination experiments were conducted with water samples from Terkos Lake (TL) and Buyukcekmece Lake (BL) (Istanbul, Turkey). The maximum loss of UV absorbance for chlorinated TL and BL raw water samples was observed at a wavelength of 272 nm. Interestingly, differential absorbance at 272 nm (Delta UV272) was shown to be a good indicator of UV absorbing chromophores and the formation of trihalomethanes (THMs) resulting from chlorination. Furthermore, differential spectra of chlorinated TL waters were similar for given chlorination conditions, peaking at 272 nm. Thecorrelations between THMs and Delta UV272 were quantified by linear equations with R-2 values >0.96. The concentration of THMs formed when natural organic matter is chlorinated increases with increasing time and pH levels. Among all THMs, CHCl3 was the dominant species forming as a result of the chlorination of TL and BL raw water samples. The highest chloroform(CHCl3), dichlorobromomethane (CHCl2 Br), and dibromochloromethane (CHBr2 Cl) concentration were released per unit loss of absorbance at 272 nm at pH 9 with a maximum reaction time of 168 hours and Cl-2/dissolved organic carbon ratio of 3.2

Seasonal variations of disinfection by-product precursors profile and their removal through surface water treatment plants

A sampling program has been undertaken to investigate the variations of disinfection by-products (DBPs) formation and nature and fate of natural organic matter (NOM) through water treatment plants in Istanbul. Specific focus has been given to the effect seasonal changes on the formation of DBPs and organic precursors levels. Water samples were collected from the three reservoirs inlet and within three major water treatment plants of Istanbul, Turkey. Changes in the dissolved organic carbon (DOC), ultraviolet absorbance at 254 nm (UV254), specific ultraviolet absorbance (SUVA), trihalomethane formation potential (THMFP), and haloacetic acids formation potential (HAAFP) were measured for both the treated and raw water samples. The variations of THM and HAA concentrations within treatment processes were monitored and also successfully assessed. The reactivity of the organic matter changed throughout the year with the lowest reactivity (THMFP and HAAFP) in winter, increasing in spring and reaching a maximum in fall season. This corresponded to the water being easier to treat in fall and an increase in the proportion of hydrophobic content. Understanding the seasonal changes in organic matter character and their reactivity with treatment chemicals should lead to a better optimization of the treatment processes and a more consistent water quality. © 2007 Elsevier B.V. All rights reserved

Monitoring and modeling of trihalomethanes (THMs) for a water treatment plant in Istanbul

Because of increasing concern for both microbial control and disinfection by-products (DBPs) formation, water utilities are strictly examining and optimizing disinfection practices. In this study, modeling of trihalomethanes (THMs) formation at processed water of the Kagithane water treatment plant in Istanbul City was conducted. Data for THMs and other water quality and operational parameters were generated through a 12-month sampling program between January and December 2003. A multiple linear regression model was developed to predict THMs concentrations in processed water. Routinely measured parameters including total organic carbon (TOC), pH, temperature, and chlorine dose were used to develop the model for the prediction of THMs. Both pH (r = 0.963) and temperature (r = 0.921) were found to be the parameters of the highest statistical significance as predictors for THMs occurrence. The regression analysis resulted in a model that is directly applicable to the chlorination of raw waters. This indicated that the linear models developed could be used to estimate THMs concentration for different water quality and treatment processes with different operational conditions

Modelling the effect of BSEP inhibitors in lipid bilayers by means of all atom Molecular Dynamics (MD) simulation

The human bile salt export pump (BSEP) is a membrane protein expressed on the canalicular plasma membrane domain of hepatocytes, which mediates active transport of unconjugated and conjugated bile salts from liver cells into bile. Genetically inherited defects in BSEP expression or activity causes cholestatic liver injury, and many drugs that cause cholestatic drug-induced liver injury (DILI) in humans have been shown to inhibit BSEP activity in vitro and in vivo, suggesting this could be one of the mechanisms that initiates human DILI. The relationship between BSEP inhibition and molecular physicochemical properties has been previously investigated identifying calculated lipophilicity and molecular weight to be significantly correlated with BSEP inhibition. Predictive BSEP classification models, constructed through multiple quantitative structure-activity relationship modeling approaches, exhibit significant anomalies with differences in experimental IC50 values of three orders of magnitude for molecules of the same calculated lipophilicity and molecular weight. The interaction of these molecules with the lipid bilayer membrane has been identified as a major contributory factor to BSEP inhibition. In this study we apply unbiased molecular dynamics (MD) simulations to study the permeation times as well as orientation preferences of BSEP inhibitors in two different lipids (saturated DMPC and unsaturated POPC). The simulations reveal that strong BSEP inhibitors have the slowest permeation times, in both POPC and DMPC, with a secondary conclusion that the time of permeation is more rapid in POPC than DMPC. The orientation of the molecules in the membrane reveals strong correlation with chemical structure, molecules containing only hydroxyl and carboxylic groups orient themselves perpendicular to the membrane whereas molecules containing nitrogen atoms exhibit no orientational preference in respect of the membrane. Finally, H-bonding interactions computed between the molecules and the membrane reveal the specific location of the molecules within the membrane