18 results found
Shmool TA, Martin LK, Bui-Le L, et al., 2021, An experimental approach probing the conformational transitions and energy landscape of antibodies: a glimmer of hope for reviving lost therapeutic candidates using ionic liquid, Chemical Science, Vol: 12, Pages: 9528-9545, ISSN: 2041-6520
Understanding protein folding in different environmental conditions is fundamentally important for predicting protein structures and developing innovative antibody formulations. While the thermodynamics and kinetics of folding and unfolding have been extensively studied by computational methods, experimental methods for determining antibody conformational transition pathways are lacking. Motivated to fill this gap, we prepared a series of unique formulations containing a high concentration of a chimeric immunoglobin G4 (IgG4) antibody with different excipients in the presence and absence of the ionic liquid (IL) choline dihydrogen phosphate. We determined the effects of different excipients and IL on protein thermal and structural stability by performing variable temperature circular dichroism and bio-layer interferometry analyses. To further rationalise the observations of conformational changes with temperature, we carried out molecular dynamics simulations on a single antibody binding fragment from IgG4 in the different formulations, at low and high temperatures. We developed a methodology to study the conformational transitions and associated thermodynamics of biomolecules, and we showed IL-induced conformational transitions. We showed that the increased propensity for conformational change was driven by preferential binding of the dihydrogen phosphate anion to the antibody fragment. Finally, we found that a formulation containing IL with sugar, amino acids and surfactant is a promising candidate for stabilising proteins against conformational destabilisation and aggregation. We hope that ultimately, we can help in the quest to understand the molecular basis of the stability of antibodies and protein misfolding phenomena and offer new candidate formulations with the potential to revive lost therapeutic candidates.
Clarke CJ, Matthews RP, Brogan APS, et al., 2021, Controlling surface chemistry and mechanical properties of metal ionogels through Lewis acidity and basicity, Journal of Materials Chemistry A, Vol: 9, Pages: 4679-4686, ISSN: 2050-7488
Ionogels are emerging as soft materials with remarkable physical properties that can be tuned to suit application requirements. The liquid component—ionic liquids—are effectively involatile, which provides new opportunities to explore gel surfaces with UHV based analytical techniques. Here, we exploit the highly solvating nature of ionic liquids to fabricate poly(ethylene glycol) based ionogels with high concentrations of zinc, and then investigate their surfaces to show that tunability extends beyond the bulk to the interface. A unique relationship between Lewis acidity and basicity and the surface concentration of metal was revealed. Chemical state analysis and molecular dynamics showed that Lewis acidic metals templated polymers to give new architectures reduced brittleness and increased flexibility, while Lewis basic metals improved polymer uniformity and strengthened gels. Therefore, bulk structure, surface composition, and metal speciation were all found to be intimately related and dependent upon the coordination strengths of ionic liquid anions. Importantly, the highly controllable surface and structural properties of metal ionogels allow fine-tuning across a broad design space, which presents new opportunities for gel based applications.
Fogarty RM, Matthews RP, Ashworth CR, et al., 2018, Experimental validation of calculated atomic charges in ionic liquids, Journal of Chemical Physics, Vol: 148, ISSN: 0021-9606
A combination of X-ray photoelectron spectroscopy and near edge X-ray absorption fine structure spectroscopy has been used to provide an experimental measure of nitrogen atomic charges in nine ionic liquids (ILs). These experimental results are used to validate charges calculated with three computational methods: charges from electrostatic potentials using a grid-based method (ChelpG), natural bond orbital population analysis, and the atoms in molecules approach. By combining these results with those from a previous study on sulfur, we find that ChelpG charges provide the best description of the charge distribution in ILs. However, we find that ChelpG charges can lead to significant conformational dependence and therefore advise that small differences in ChelpG charges (<0.3 e) should be interpreted with care. We use these validated charges to provide physical insight into nitrogen atomic charges for the ILs probed.
Fogarty RM, Matthews RP, Clough MT, et al., 2017, NEXAFS spectroscopy of ionic liquids: experiments versus calculations, Physical Chemistry Chemical Physics, Vol: 19, Pages: 31156-31167, ISSN: 1463-9076
Experimental near edge X-ray absorption fine structure (NEXAFS) spectra are reported for 12 ionic liquids (ILs) encompassing a range of chemical structures for both the sulfur 1s and nitrogen 1s edges and compared with time-dependent density functional theory (TD-DFT) calculations. The energy scales for the experimental data were carefully calibrated against literature data. Gas phase calculations were performed on lone ions, ion pairs and ion pair dimers, with a wide range of ion pair conformers considered. For the first time, it is demonstrated that TD-DFT is a suitable method for simulating NEXAFS spectra of ILs, although the number of ions included in the calculations and their conformations are important considerations. For most of the ILs studied, calculations on lone ions in the gas phase were sufficient to successfully reproduce the experimental NEXAFS spectra. However, for certain ILs – for example, those containing a protic ammonium cation – calculations on ion pairs were required to obtain a good agreement with experimental spectra. Furthermore, significant conformational dependence was observed for the protic ammonium ILs, providing insight into the predominant liquid phase cation–anion interactions. Among the 12 investigated ILs, we find that four have an excited state that is delocalised across both the cation and the anion, which has implications for any process that depends on the excited state, for example, radiolysis. Considering the collective experimental and theoretical data, we recommend that ion pairs should be the minimum number of ions used for the calculation of NEXAFS spectra of ILs.
Brooks NJ, Castiglione F, Doherty CM, et al., 2017, Linking the structures, free volumes, and properties of ionic liquid mixtures, Chemical Science, Vol: 8, Pages: 6359-6374, ISSN: 2041-6520
The formation of ionic liquid (IL) mixtures has been proposed as an approach to rationally fine-tune the physicochemical properties of ILs for a variety of applications. However, the effects of forming such mixtures on the resultant properties of the liquids are only beginning to be understood. Towards a more complete understanding of both the thermodynamics of mixing ILs and the effect of mixing these liquids on their structures and physicochemical properties, the spatial arrangement and free volume of IL mixtures containing the common [C4C1im]+ cation and different anions have been systematically explored using small angle X-ray scattering (SAXS), positron annihilation lifetime spectroscopy (PALS) and 129Xe NMR techniques. Anion size has the greatest effect on the spatial arrangement of the ILs and their mixtures in terms of the size of the non-polar domains and inter-ion distances. It was found that differences in coulombic attraction between oppositely charged ions arising from the distribution of charge density amongst the atoms of the anion also significantly influences these inter-ion distances. PALS and 129Xe NMR results pertaining to the free volume of these mixtures were found to strongly correlate with each other despite the vastly different timescales of these techniques. Furthermore, the excess free volumes calculated from each of these measurements were in excellent agreement with the excess volumes of mixing measured for the IL mixtures investigated. The correspondence of these techniques indicates that the static and dynamic free volume of these liquid mixtures are strongly linked. Consequently, fluxional processes such as hydrogen bonding do not significantly contribute to the free volumes of these liquids compared to the spatial arrangement of ions arising from their size, shape and coulombic attraction. Given the relationship between free volume and transport properties such as viscosity and conductivity, these results provide a link between the s
Fogarty RM, Rowe R, Matthews RP, et al., 2017, Atomic charges of sulfur in ionic liquids: experiments and calculations, Faraday Discussions, Vol: 206, Pages: 183-201, ISSN: 1359-6640
Experimental near edge X-ray absorption fine structure (NEXAFS) spectra, X-ray photoelectron (XP) spectra and Auger electron spectra are reported for sulfur in ionic liquids (ILs) with a range of chemical structures. These values provide experimental measures of the atomic charge in each IL and enable the evaluation of the suitability of NEXAFS spectroscopy and XPS for probing the relative atomic charge of sulfur. In addition, we use Auger electron spectroscopy to show that when XPS binding energies differ by less than 0.5 eV, conclusions on atomic charge should be treated with caution. Our experimental data provides a benchmark for calculations of the atomic charge of sulfur obtained using different methods. Atomic charges were computed for lone ions and ion pairs, both in the gas phase (GP) and in a solvation model (SMD), with a wide range of ion pair conformers considered. Three methods were used to compute the atomic charges: charges from the electrostatic potential using a grid based method (ChelpG), natural bond orbital (NBO) population analysis and Bader’s atoms in molecules (AIM) approach. By comparing the experimental and calculated measures of the atomic charge of sulfur, we provide an order for the sulfur atoms, ranging from the most negative to the most positive atomic charge. Furthermore, we show that both ChelpG and NBO are reasonable methods for calculating the atomic charge of sulfur in ILs, based on the agreement with both the XPS and NEXAFS spectroscopy results. However, the atomic charges of sulfur derived from ChelpG are found to display significant, non-physical conformational dependence. Only small differences in individual atomic charge of sulfur were observed between lone ion (GP) and ion pair IL(SMD) model systems, indicating that ion–ion interactions do not strongly influence individual atomic charges.
Hunt PA, Ashworth C, Matthews R, et al., 2016, Doubly Ionic Hydrogen Bond Interactions Within the Choline Chloride - Urea Deep Eutectic Solvent, Physical Chemistry Chemical Physics, Vol: 18, Pages: 18145-18160, ISSN: 1463-9084
Deep eutectic solvents (DESs) are exemplars of systems with the ability to form neutral, ionic and doubly ionic H-bonds. Herein, the pairwise interactions of the constituent components of the choline chloride–urea DES are examined. Evidence is found for a tripodal CH⋯Cl doubly ionic H-bond motif. Moreover it is found that the covalency of doubly ionic H-bonds can be greater than, or comparable with, neutral and ionic examples. In contrast to many traditional solvents, an “alphabet soup” of many different types of H-bond (OH⋯O[double bond, length as m-dash]C, NH⋯O[double bond, length as m-dash]C, OH⋯Cl, NH⋯Cl, OH⋯NH, CH⋯Cl, CH⋯O[double bond, length as m-dash]C, NH⋯OH and NH⋯NH) can form. These H-bonds exhibit substantial flexibility in terms of number and strength. It is anticipated that H-bonding will have a significant impact on the entropy of the system and thus could play an important role in the formation of the eutectic. The 2 : 1 urea : choline–chloride eutectic point of this DES is often associated with the formation of a [Cl(urea)2]− complexed anion. However, urea is found to form a H-bonded urea[choline]+ complexed cation that is energetically competitive with [Cl(urea)2]−. The negative charge on [Cl(urea)2]− is found to remain localised on the chloride, moreover, the urea[choline]+ complexed cation forms the strongest H-bond studied here. Thus, there is potential to consider a urea[choline]+·urea[Cl]− interaction.
Welton T, Matthews RP, Villar-Garcia IJ, et al., 2016, A structural investigation of ionic liquid mixtures, Physical Chemistry Chemical Physics, Vol: 18, Pages: 8608-8624, ISSN: 1463-9084
The structures of mixtures of ionic liquids (ILs) featuring a common 1-butyl-3-methylimidazolium ([C4C1im]+) cation butdifferent anions have been investigated both experimentally and computationally. 1H and 13C NMR of the ILs and theirmixtures has been performed both on the undiluted liquids and these diluted by CD2Cl2. These experiments have beencomplemented by quantum chemical density functional theory calculations and molecular dynamics simulations. Thesetechniques have identified the formation of preferential interactions between H2 of the imidazolium cation and the moststrongly hydrogen bond (H-bond) accepting anion. In addition, a preference for the more weakly H-bond accepting anionto interact above the imidazolium ring through anion-π+ interactions has been identified. The modelling of these data hasidentified that the magnitude of these preferences are small, of the order of only a few kJ mol−1, for all IL mixtures. Noclustering of the anions around a specific cation could be observed, indicating that these interactions arise from thereorientation of the cation within a randomly assigned network of anions. π+-π+ stacking of the imidazolium cations wasalso studied and found to be promoted by ILs with a strong H-bond accepting anion. Stacking interactions are easilydisrupted by the introduction of small proportions (< 50 mol%) of a weakly coordinating anion due to their propensity toform anion-π+ interactions. These results suggest that the formation of IL mixtures with different anions leads to subtlestructural changes of much lower energy than the Coulombic ordering of ions, accounting for why most IL mixtures exhibitideal, or nearly ideal, behaviour.
Hunt PA, Ashworth CR, Matthews RP, 2015, Hydrogen bonding in ionic liquids, CHEMICAL SOCIETY REVIEWS, Vol: 44, Pages: 1257-1288, ISSN: 0306-0012
Xue L, Tamas G, Matthews RP, et al., 2015, An OHD-RIKES and simulation study comparing a benzylmethylimidazolium ionic liquid with an equimolar mixture of dimethylimidazolium and benzene, Physical Chemistry Chemical Physics, Vol: 17, Pages: 9973-9983, ISSN: 1463-9084
The principal difference between 1-benzyl-3-methyl-imidazolium triflimide [BzC1im][NTf2] and an equimolar mixture of benzene and dimethylimidazolium triflimide [C1C1im][NTf2] is that in the former the benzene moieties are tied to the imidazolium ring, while in the latter they move independently. We use femtosecond optical heterodyne-detected Raman-induced Kerr effect spectroscopy (OHD-RIKES) and molecular simulations to explore some properties of these two systems. The Kerr spectra show small differences in the spectral densities; the simulations also show very similar environments for both the imidazolium rings and the phenyl or benzene parts of the molecules. The low frequency vibrational densities of states are also similar in the model systems. In order to perform the simulations we developed a model for the [BzC1im]+ cation and found that the barriers to rotation of the two parts of the molecule are low.
Matthews RP, Welton T, Hunt PA, 2015, Hydrogen bonding and pi-pi interactions in imidazolium-chloride ionic liquid clusters, PHYSICAL CHEMISTRY CHEMICAL PHYSICS, Vol: 17, Pages: 14437-14453, ISSN: 1463-9076
Matthews RP, Ashworth C, Welton T, et al., 2014, The impact of anion electronic structure: similarities and differences in imidazolium based ionic liquids, JOURNAL OF PHYSICS-CONDENSED MATTER, Vol: 26, ISSN: 0953-8984
Matthews RP, Welton T, Hunt PA, 2014, Competitive pi interactions and hydrogen bonding within imidazolium ionic liquids, PHYSICAL CHEMISTRY CHEMICAL PHYSICS, Vol: 16, Pages: 3238-3253, ISSN: 1463-9076
Skarmoutsos I, Dellis D, Matthews RP, et al., 2012, Hydrogen Bonding in 1-Butyl- and 1-Ethyl-3-methylimidazolium Chloride Ionic Liquids, The Journal of Physical Chemistry B, Vol: 116, Pages: 4921-4933-4921-4933
Fehér K, Matthews RP, Kövér KE, et al., 2011, Conformational preferences in diglycosyl disulfides: NMR and molecular modeling studies, Carbohydrate Research, Vol: 346, Pages: 2612-2621, ISSN: 0008-6215
Matthews RP, Venter GA, Naidoo KJ, 2011, Using Solvent Binding and Dielectric Friction To Interpret the Hydration Behavior of Complex Anions, The Journal of Physical Chemistry B, Vol: 115, Pages: 1045-1055, ISSN: 1520-6106
Matthews RP, Naidoo KJ, 2010, Experimentally Consistent Ion Association Predicted for Metal Solutions from Free Energy Simulations, The Journal of Physical Chemistry B, Vol: 114, Pages: 7286-7293, ISSN: 1520-6106
Venter GA, Matthews RP, Naidoo KJ, 2008, Conformational flexibility of sulphur linked saccharides a possible key to their glycosidase inhibitor activity, Molecular Simulation, Vol: 34, Pages: 391-402, ISSN: 0892-7022
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