A computational methodology that couples the acidity (Ka) and density functional theory (DFT) cal... more A computational methodology that couples the acidity (Ka) and density functional theory (DFT) calculations has been developed to explain the pH-dependent drug loading on and releasing from mesoporous silica nanoparticles.
Herein, we present a theoretical model that combines classical pKa theory with quantum mechanical... more Herein, we present a theoretical model that combines classical pKa theory with quantum mechanical calculations to predict the extent of interaction between acid-/base-dependent species over a full range of pH conditions. To demonstrate the theoretical model, we have predicted the drug loading and release of a pH-responsive drug delivery system consisting of sulfasalazine, an anionic anti-inflammatory drug molecule, loaded onto the positively charged trimethylammonium (TA)-functionalized mesoporous silica nanoparticle surface. The model relies on the possible combinations of pH-dependent states of the surface (S) and drug (D) molecules as neutral (0) and deprotonated (−1) states, whose relative probabilities depend on their pKa value and the desired pH. The four possible combinations were identified as S0D0, S0D–1, S–1D0, and S–1D–1, and periodic density functional theory calculations were performed for systems comprising drug fragments adsorbed onto a model TA-functionalized quartz surface to calculate th...
... DOI: 10.1080/17441690701191693 AA Skelton a * & TR Walsh a pages 379-389.... more ... DOI: 10.1080/17441690701191693 AA Skelton a * & TR Walsh a pages 379-389. ... J. Phys. Chem. B , : 6160 [CrossRef], [PubMed], [Web of Science ®] View all references]. The authors used TIP3P water in conjunction with the AMBER force-field [2323. ...
This work investigates NOTA–alkali metal (Li+, Na+ and K+ and Rb+) complexation using density fun... more This work investigates NOTA–alkali metal (Li+, Na+ and K+ and Rb+) complexation using density functional theory.
This work involves the experimental and theoretical study of the nucleophilic substitution of met... more This work involves the experimental and theoretical study of the nucleophilic substitution of meta- and para-substituted benzyl bromides with benzylamine. Conductometric rate experiments confirm the applicability of the Hammett linear free-energy relationship to this system. To gain a deep understanding of the physical chemistry at play, a quantum mechanical study of the reaction is also conducted. The quantum mechanical calculations not only reproduce the experimental free energy of activation, but also provide greater insights at the molecular and atomic level. Isolation of the calculated transition state structure and application of the Hammett equation to its electronic, structural, and energetic properties are studied.
Two different terminations of the (1010) surface of quartz (α and β) interacting with water are s... more Two different terminations of the (1010) surface of quartz (α and β) interacting with water are simulated by classical (CMD) (using two different force fields) and ab initio molecular dynamics (AIMD) and compared with previously published X-ray reflectivity (XR) experiments. Radial distribution functions between hydroxyl and water show good agreement between AIMD and CMD using the ClayFF force field for both terminations. The Lopes et al. (Lopes, P. E. M.; Murashov, V.; Tazi, M.; Demchuk, E.; MacKerell, A. D. J. Phys. Chem. B2006, 110, 2782-2792) force field (LFF), however, underestimates the extent of hydroxyl-water hydrogen bonding. The β termination is found to contain hydroxyl-hydroxyl hydrogen bonds; the quartz surface hydroxyl hydrogens and oxygens that hydrogen bond with each other exhibit greatly reduced hydrogen bonding to water. Conversely, the hydroxyl hydrogen and oxygens that are not hydrogen bonded to other surface hydroxyls but are connected to those that are show a considerable amount of hydrogen bonding to water. The electron density distribution of an annealed surface of quartz (1010) obtained by XR is in qualitative agreement with electron densities calculated by CMD and AIMD. In all simulation methods, the interfacial water peak appears farther from the surface than observed by XR. Agreement among AIMD, LFF, and XR is observed for the relaxation of the near-surface atoms; however, ClayFF shows a larger discrepancy. Overall, results show that for both terminations of (1010), LFF treats the near-surface structure more accurately whereas ClayFF treats the interfacial water structure more accurately. It is shown that the number of hydroxyl and water hydrogen bonds to the bridging Si-O-Si oxygens connecting the surface silica groups to the rest of the crystal is much greater for the α than the β termination. It is suggested that this may play a role in the greater resistance to dissolution of the β termination than that of the α termination.
The synthesis and structural characterisation of novel imino cyclophanes incorporating various sp... more The synthesis and structural characterisation of novel imino cyclophanes incorporating various spacer units is described. All the imino cyclophanes exhibit comparable antibacterial activity against Gram positive (Bacillus subtillus, Staphylococcus aureus) and Gram negative (Escherchia coli, Klebsiella pneumonia) bacterial strains. The imino cyclophanes also exhibit good antifungal activity against human pathogenic fungus, Candida albicans.
1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetracetic acid (DOTA) is an important chelator for... more 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetracetic acid (DOTA) is an important chelator for radiolabeling of pharmaceuticals. The ability of alkali metals, found in the body, to complex with DOTA and compete with radio metals can alter the radiolabeling process. Non-covalent interactions between DOTA complexed with alkali metals, Li, Na, K and Rb, were investigated with density functional theory using B3LYP and ωB97XD functionals with 6-311+G (2d, 2p) basis set for Li, Na and K and Def2-TZVPD for Rb. Conformational possibilities were explored in terms of a different number of carboxylic pendant arms of DOTA in in close proximity to the ions. It is found that the case in which four arms of DOTA are interacting with ions is more stable in comparison to other
Density functional theory (DFT) calculations using the B3LYP and ωB97XD functionals and Møller-Pl... more Density functional theory (DFT) calculations using the B3LYP and ωB97XD functionals and Møller-Plesset (MP2) calculations have been used to determine the energy of insertion of seven molecules (CO2, N2, O2, CO, CH4, He and H2O) into two sizes of polyhedral oligomeric silsesquioxane (POSS) cages, T10 and T12. Geometry optimization results of each molecule inserted into the center of the POSS cage and transition-energy searches of the molecules in the largest face of both T10 and T12 (identified as the Si5 face) are discussed. The main factors that affect the energy of a molecule in a particular POSS cage are the size (number of atoms) and shape of the POSS cage and the strength of dispersion and electrostatic interactions. The largest of the molecules, CO2 and CH4, have the largest interaction energies within the center and the face of the T10 and T12 cages. Interaction energies for the diatomic molecules increase in the order H2 < O2 < N2 ∼ CO and differences between interaction energies can be attributed, in part, to differences in electron transfer between the cage and molecule. Electrostatic interactions also play a significant role in determining the interaction energy. For example, H2 and He are only slightly charged when inside the POSS cages, providing little repulsive or attractive interactions, while polar CO provides significant repulsive interaction. In the case of water, the interaction energies are low because of hydrogen bonding between the water hydrogen atoms and the POSS oxygen atoms. The interaction energies of the absorbates at the center of T12 are typically smaller than for T10 due to the larger cavity size of T12. The Si5 face has the same basic structure for both T10 and T12 cages and, consequently, the interaction energies of the absorbate molecules at the face are similar. Interaction energies obtained using MP2 calculations are lower than those obtained from DFT calculations depending on the choice of the functional. For example, use of the ωB97XD functional that treats dispersion interactions more completely than the B3LYP functional, produces values closer to the MP2 values. These results, therefore, suggest that dispersion is important in the interaction between small molecules and POSS cages.
pKas of P(1)-H deprotonation of all phosphole group compounds, phosphole (C4H4PH), 1,2 and 1,3-di... more pKas of P(1)-H deprotonation of all phosphole group compounds, phosphole (C4H4PH), 1,2 and 1,3-diphospholes (C3H3PPH), 1,2,3, and 1,2,4-triphospholes (C2H2P2PH), tetraphosphole (CHP3PH), and pentaphosphole (P4PH) are determined by DFT calculations. We have compared these to the pKas of the analogue azole group compounds and the factors that cause the differences of these values are discussed in terms of the stabilities of both the phosphole anions and azole anions.
A computational methodology that couples the acidity (Ka) and density functional theory (DFT) cal... more A computational methodology that couples the acidity (Ka) and density functional theory (DFT) calculations has been developed to explain the pH-dependent drug loading on and releasing from mesoporous silica nanoparticles.
Herein, we present a theoretical model that combines classical pKa theory with quantum mechanical... more Herein, we present a theoretical model that combines classical pKa theory with quantum mechanical calculations to predict the extent of interaction between acid-/base-dependent species over a full range of pH conditions. To demonstrate the theoretical model, we have predicted the drug loading and release of a pH-responsive drug delivery system consisting of sulfasalazine, an anionic anti-inflammatory drug molecule, loaded onto the positively charged trimethylammonium (TA)-functionalized mesoporous silica nanoparticle surface. The model relies on the possible combinations of pH-dependent states of the surface (S) and drug (D) molecules as neutral (0) and deprotonated (−1) states, whose relative probabilities depend on their pKa value and the desired pH. The four possible combinations were identified as S0D0, S0D–1, S–1D0, and S–1D–1, and periodic density functional theory calculations were performed for systems comprising drug fragments adsorbed onto a model TA-functionalized quartz surface to calculate th...
... DOI: 10.1080/17441690701191693 AA Skelton a * & TR Walsh a pages 379-389.... more ... DOI: 10.1080/17441690701191693 AA Skelton a * & TR Walsh a pages 379-389. ... J. Phys. Chem. B , : 6160 [CrossRef], [PubMed], [Web of Science ®] View all references]. The authors used TIP3P water in conjunction with the AMBER force-field [2323. ...
This work investigates NOTA–alkali metal (Li+, Na+ and K+ and Rb+) complexation using density fun... more This work investigates NOTA–alkali metal (Li+, Na+ and K+ and Rb+) complexation using density functional theory.
This work involves the experimental and theoretical study of the nucleophilic substitution of met... more This work involves the experimental and theoretical study of the nucleophilic substitution of meta- and para-substituted benzyl bromides with benzylamine. Conductometric rate experiments confirm the applicability of the Hammett linear free-energy relationship to this system. To gain a deep understanding of the physical chemistry at play, a quantum mechanical study of the reaction is also conducted. The quantum mechanical calculations not only reproduce the experimental free energy of activation, but also provide greater insights at the molecular and atomic level. Isolation of the calculated transition state structure and application of the Hammett equation to its electronic, structural, and energetic properties are studied.
Two different terminations of the (1010) surface of quartz (α and β) interacting with water are s... more Two different terminations of the (1010) surface of quartz (α and β) interacting with water are simulated by classical (CMD) (using two different force fields) and ab initio molecular dynamics (AIMD) and compared with previously published X-ray reflectivity (XR) experiments. Radial distribution functions between hydroxyl and water show good agreement between AIMD and CMD using the ClayFF force field for both terminations. The Lopes et al. (Lopes, P. E. M.; Murashov, V.; Tazi, M.; Demchuk, E.; MacKerell, A. D. J. Phys. Chem. B2006, 110, 2782-2792) force field (LFF), however, underestimates the extent of hydroxyl-water hydrogen bonding. The β termination is found to contain hydroxyl-hydroxyl hydrogen bonds; the quartz surface hydroxyl hydrogens and oxygens that hydrogen bond with each other exhibit greatly reduced hydrogen bonding to water. Conversely, the hydroxyl hydrogen and oxygens that are not hydrogen bonded to other surface hydroxyls but are connected to those that are show a considerable amount of hydrogen bonding to water. The electron density distribution of an annealed surface of quartz (1010) obtained by XR is in qualitative agreement with electron densities calculated by CMD and AIMD. In all simulation methods, the interfacial water peak appears farther from the surface than observed by XR. Agreement among AIMD, LFF, and XR is observed for the relaxation of the near-surface atoms; however, ClayFF shows a larger discrepancy. Overall, results show that for both terminations of (1010), LFF treats the near-surface structure more accurately whereas ClayFF treats the interfacial water structure more accurately. It is shown that the number of hydroxyl and water hydrogen bonds to the bridging Si-O-Si oxygens connecting the surface silica groups to the rest of the crystal is much greater for the α than the β termination. It is suggested that this may play a role in the greater resistance to dissolution of the β termination than that of the α termination.
The synthesis and structural characterisation of novel imino cyclophanes incorporating various sp... more The synthesis and structural characterisation of novel imino cyclophanes incorporating various spacer units is described. All the imino cyclophanes exhibit comparable antibacterial activity against Gram positive (Bacillus subtillus, Staphylococcus aureus) and Gram negative (Escherchia coli, Klebsiella pneumonia) bacterial strains. The imino cyclophanes also exhibit good antifungal activity against human pathogenic fungus, Candida albicans.
1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetracetic acid (DOTA) is an important chelator for... more 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetracetic acid (DOTA) is an important chelator for radiolabeling of pharmaceuticals. The ability of alkali metals, found in the body, to complex with DOTA and compete with radio metals can alter the radiolabeling process. Non-covalent interactions between DOTA complexed with alkali metals, Li, Na, K and Rb, were investigated with density functional theory using B3LYP and ωB97XD functionals with 6-311+G (2d, 2p) basis set for Li, Na and K and Def2-TZVPD for Rb. Conformational possibilities were explored in terms of a different number of carboxylic pendant arms of DOTA in in close proximity to the ions. It is found that the case in which four arms of DOTA are interacting with ions is more stable in comparison to other
Density functional theory (DFT) calculations using the B3LYP and ωB97XD functionals and Møller-Pl... more Density functional theory (DFT) calculations using the B3LYP and ωB97XD functionals and Møller-Plesset (MP2) calculations have been used to determine the energy of insertion of seven molecules (CO2, N2, O2, CO, CH4, He and H2O) into two sizes of polyhedral oligomeric silsesquioxane (POSS) cages, T10 and T12. Geometry optimization results of each molecule inserted into the center of the POSS cage and transition-energy searches of the molecules in the largest face of both T10 and T12 (identified as the Si5 face) are discussed. The main factors that affect the energy of a molecule in a particular POSS cage are the size (number of atoms) and shape of the POSS cage and the strength of dispersion and electrostatic interactions. The largest of the molecules, CO2 and CH4, have the largest interaction energies within the center and the face of the T10 and T12 cages. Interaction energies for the diatomic molecules increase in the order H2 < O2 < N2 ∼ CO and differences between interaction energies can be attributed, in part, to differences in electron transfer between the cage and molecule. Electrostatic interactions also play a significant role in determining the interaction energy. For example, H2 and He are only slightly charged when inside the POSS cages, providing little repulsive or attractive interactions, while polar CO provides significant repulsive interaction. In the case of water, the interaction energies are low because of hydrogen bonding between the water hydrogen atoms and the POSS oxygen atoms. The interaction energies of the absorbates at the center of T12 are typically smaller than for T10 due to the larger cavity size of T12. The Si5 face has the same basic structure for both T10 and T12 cages and, consequently, the interaction energies of the absorbate molecules at the face are similar. Interaction energies obtained using MP2 calculations are lower than those obtained from DFT calculations depending on the choice of the functional. For example, use of the ωB97XD functional that treats dispersion interactions more completely than the B3LYP functional, produces values closer to the MP2 values. These results, therefore, suggest that dispersion is important in the interaction between small molecules and POSS cages.
pKas of P(1)-H deprotonation of all phosphole group compounds, phosphole (C4H4PH), 1,2 and 1,3-di... more pKas of P(1)-H deprotonation of all phosphole group compounds, phosphole (C4H4PH), 1,2 and 1,3-diphospholes (C3H3PPH), 1,2,3, and 1,2,4-triphospholes (C2H2P2PH), tetraphosphole (CHP3PH), and pentaphosphole (P4PH) are determined by DFT calculations. We have compared these to the pKas of the analogue azole group compounds and the factors that cause the differences of these values are discussed in terms of the stabilities of both the phosphole anions and azole anions.
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