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

On the selection and design of proteins and peptide derivatives for the production of photoluminescent, red-emitting gold quantum clusters

Novel pathways of the synthesis of photoluminescent gold quantum clusters (AuQCs) using biomolecules as reactants provide biocompatible products for biological imaging techniques. In order to rationalize the rules for the preparation of red-emitting AuQCs in aqueous phase using proteins or peptides, the role of different organic structural units was investigated. Three systems were studied: proteins, peptides, and amino acid mixtures, respectively. We have found that cysteine and tyrosine are indispensable residues. The SH/S-S ratio in a single molecule is not a critical factor in the synthesis, but on the other hand, the stoichiometry of cysteine residues and the gold precursor is crucial. These observations indicate the importance of proper chemical behavior of all species in a wide size range extending from the atomic distances (in the AuI-S semi ring) to nanometer distances covering the larger sizes of proteins assuring the hierarchical structure of the whole self-assembled system

The thermal expansion coefficients of the alpha and beta polymorphic forms of p-aminobenzoic acid in relation to their bulk crystal chemistry

The thermal expansion behaviour of the alpha and beta polymorphs of para-aminobenzoic acid are presented and discussed in terms of the bulk crystal chemistry and the associated strengths of the constituent intermolecular synthons for these two materials. Analysis of temperature dependant powder diffraction data over the temperature range 298.15–403.15 K facilitates calculation of the linear thermal expansion coefficients: αa = 8.36 × 10−06 K−1, αb = 94.5 × 10−06 K−1 and αc = 9.91 × 10−06 K−1 for the alpha polymorph and αa = 21.5 × 10−06 K−1, αb = 48.5 × 10−06 K−1 and αc = 2.22 × 10−06 K−1 for the beta polymorph. The exceptionally large increase in the thermal expansion of the b axis for the alpha form reflects the weak dispersive interactions which propagate along this axis. In contrast, the a and c axes contain relatively strong hydrogen bonds which stabilise the lattice and limit thermal expansion. The thermal expansion of the beta form reflects the more isotropic nature of the intermolecular synthons for this polymorph in comparison to the alpha form. The thermal expansion of the b axis of the beta form is larger than that of the a and c axes but to a much lesser extent than that observed for the alpha form. This is rationalised through identification of a hydrogen bonding component which contributes to the stabilisation of the b axis in comparison to the almost fully dispersive nature found in the alpha structure

Crystallisation route map

A route map for the assessment of crystallisation processes is presented. A theoretical background on solubility, meta-stable zone width, nucleation and crystal growth kinetics is presented with practical examples. The concepts of crystallisation hydrodynamics and the application of population balances and computational fluid dynamics for modelling crystallisation processes and their scaling up are also covered

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

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

The effect of the oxidation state of the metal center in metalloporphyrins on the electrocatalytic CO<inf>2</inf>-to-CO conversion: A density functional theory study

© 2020 Elsevier B.V. Metalloporphyrins are a promising and sustainable class of molecular catalysts for the transformation of CO2 into value-added chemicals whereby the catalytic process is tuneable through the modification of the peripheral ligands and the electronic properties of the metal centre. In this work, we studied the electrochemical reduction of CO2 on metalloporphyrins using computational modelling. Density functional theory calculations were used to characterize the mechanism of 2-electron CO2-to-CO conversion on three metalloporphyrins [M-POR] catalysts, where M = Fe, Co and Ni, with the initial CO2 adsorption step taking place on the metal center in the neutral, [M-POR]0, singly reduced [M-POR]−, and doubly reduced, [M-POR]2−, oxidation states. The three alternative pathways display different energetic trends. In general, the catalytic activity for CO formation on metalloporphyrins in the neutral oxidation state, [M-POR]0, is negatively influenced by the conversion of CO2 to adsorbate formate, which is hindered by the weak *C(OH)O binding. The more favorable association of CO2 and strong stabilization of *C(OH)O occurs on the catalysts in the doubly reduced oxidation state, [M-POR]2−. Higher Faraday efficiencies for CO formation could be achieved under electrochemical conditions promoting well-reduced metal species

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

New insights into the role of solution additive anions in Mg2+ dehydration: implications for mineral carbonation

Simulations of hydrated Mg2+, in the absence and presence of several solution additive anions, show that in pure liquid water Mg(H2O)62+ is the only stable coordination state; yet anions may stabilise undercoordinated five-hydration configurations. Solution composition can lower the barrier to Mg2+ dehydration and subsequent incorporation into the lattice of Mg-carbonates, promoting low-temperature crystallisation