Chemical Sciences

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An analysis of quenching and extraction techniques for performing metabolomics in Acidithiobacillus ferrooxidans.
(2016-10-07) Doran, Marney Lynn
I present here a protocol for accurate liquid chromatography – mass spectrometry based determination of the metabolome of Acidithiobacillus ferrooxidans. At. ferrooxidans metabolic processes contribute to the environmentally destructive process of acid mine drainage (AMD), and metabolomic profiling can offer insight into how At. ferrooxidans contributes to these processes. Metabolism must be stopped (quenched) instantaneously while limiting the amount of cell damage. I tested a wide variety of quenching solutions and found that ammonium formate was the most effective quenching solution. An accurate metabolomics analysis also requires extraction of as large a number of metabolites as possible, with as little chemical bias (in extraction or degradation) as possible. I tested a wide variety of extraction solutions and found that isopropanol:methanol:water was the best extraction solution. Standardizing a protocol to quench and extract metabolites in At. ferrooxidans will contribute to understanding how At. ferrooxidans contributes to the AMD phenomenon.
Analysis of tramadol and its metabolites in rat skeletal tissues following acute and repeated dose patterns using high performance liquid chromatography tandem mass spectrometry
(2020-10-15) Buckingham, Christian L.
The use of skeletal elements for the viable analysis of drugs of abuse has seen increased prevalence in the past 10 years. Advancements in the analytical methods used, including solid phase extraction and mass spectrometry, have allowed for increased sensitivity and selectivity. Previous studies have focused on the influence of dose-death interval, microclimate, differential patterns of exposure, and the influence of body position. In this work, the opioid analgesic tramadol was investigated for its pharmacological behaviour when administered as part of three dosage patterns to male Sprague Dawley rats. The three exposure patterns consisted of an acute low (n = 4, 1 doses, 30 mg/kg) group, a repeated high survived group (n = 5, 3 doses, 30 mg/kg) and a repeated high overdosed group (n = 11, 3 doses, 30 mg/kg). Drug free rats (n = 4) served as negative controls. Following euthanasia by CO2 asphyxiation, animals were decomposed to skeleton outdoors over the summer of 2019 in Sudbury, Ontario. Bones were sorted by animal and skeletal element (skull, vertebrae, ribs, pelvis, femur, tibia/fibula), then washed and ground to powder before undergoing dynamic methanolic extraction. Semi-quantitative analysis of tramadol and four of its metabolites – O-desmethyltramadol, N-desmethyltramadol, N,Odidesmethyltramadol and tramadol N-oxide – was conducted using high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) in positive ion mode. Analyte levels were expressed as a mass-normalized response ratio (RR/m) in order to account for the exact mass of bone used. Method validation for the analysis of tramadol and its metabolites was investigated in accordance with the Scientific Working Group of Toxicologists (SWGTOX) standards of practice, with all criteria except for dilution integrity successfully met at a limit of detection and limit of quantitation of 1 ng/mL. The effect of exposure pattern on analyte level and analyte level ratio was assessed using the Kruskal-Wallis test for significant differences (P < 0.05). A total of 315 pairwise comparisons were performed to assess significant differences, with the ratio of tramadol to N-desmethyltramadol determined to be the metric most commonly able to identify these differences in 91% of tests. Additionally, the effect of skeletal element on analyte level and analyte level ratio was also assessed, with a total of 675 pairwise comparisons. Skeletal element was determined to be a significant factor in all cases. This data suggests that both skeletal element and dose pattern are important measures to evaluate with respect to the analysis of drugs of abuse in bone tissues. Furthermore, different metrics, including analyte level and analyte level ratios, may be useful for discriminating between these different dosing patterns.
Challenges in method development for analysis of selected phenothizaine drugs in biological samples: oxidation of drugs and metabolites during sample preparation
(2017-04-10) Campbell, Courtney
The main goal of this research project was the detection and semi-quantitation of the parent drugs promethazine (PMZ), and chlorpromazine(CPZ) along with selected metabolites promethazine sulfoxide (PMZSO), desmethylpromethazine (DPMZ), chlorpromazine sulfoxide (CPZSO), and desmethylchlorpromazine (DCPZ) in the skeletal remains of rats. We sought to evaluate the relative distribution of structural analogues (promethazine (PMZ) and chlorpromazine (CPZ)), and the relationship of multiple metabolites to the parent drug. The first phase of the project was to consist of method development and validation and the second phase would be examining a large number of rat bone samples exposed to different drug exposure patterns. For the analytical method, drug extraction is completed using microwave assisted extraction (MAE), followed by sample clean-up by microplate solid-phase extraction (MPSPE) and instrumental analysis by ultra-high performance liquid chromatography coupled to photodiode array detection (UHPLC-PDA). During method development and validation, extraneous compounds appeared in the chromatograms. The production of unknown compounds hindered the ability to meet the validation criteria. Thus, the new objective of the research was characterization of the unknown compounds by ultra-high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-qTOF-MS), comparing the extent of degradation for different extraction conditions, and validation of a new method that does not promote degradation.
Comparison of multiple drug and metabolite levels recovered from skeletonized remains following standard passive extraction, microwave-assisted extraction and ultrasonic solvent extraction and GC-MS or UPLC-DAD
(Laurentian University of Sudbury, 2014-03-17) Betit, Caroline
Computer simulation of molecular shape transitions in adsorbed polymers under confinement conditions
(2017-08-28) Harrison, Jessica Elena
The structural and dynamical properties of polymer-covered surfaces under confinement and crowding effects are key to many applications. Earlier work showed the occurrence of “escape transitions” in small uncompressed clusters (or “islands”) even for repulsive polymers. These transitions involve a switch from evenly-compact configurations (“trapped chains”), to uneven compactness (“escaped chains”). Here, we address a complementary question: if the crowding is reduced by having fewer neighbours, can an external compression produce “escaped configurations”? To this end, we focused on the confinement of grafted polymers. At low compression, the inter-chain entanglement increases with excluded volume as chains swell and interpenetrate, up to a critical chain length where the behaviour is reversed. We conclude that, when few chains are present or if a larger ensemble of them is arranged symmetrically, compression induces chain avoidance without inducing escape transitions. The switch in mechanism depends mostly on crowding, and not on the applied pressure.
Deposition and characterization of mesoporous silica coatings on magnesium alloys
(Laurentian University of Sudbury, 2014-03-17) Al Hegy, Afrah
In recent years, magnesium and magnesium alloys have received much attention as a new biomaterial in orthopaedic applications due to their biodegradability, biocompatibility, and their mechanical properties that are similar to natural bone tissue. The most common problem associated with magnesium as a biomaterial is low corrosion resistance in physiological solutions. This decreases the mechanical integrity of the implants in the early stages of healing and has a negative impact on the overall biocompatibility. The main goal of this study was to create a multi-layered coating consisting of a silica sol-gel under-layer to protect the substrate from corrosion in body fluids and a mesoporous silica top-layer to enhance the bioactivity of the coated implant material. The results indicate that the deposited multi-layered coating enhances both the bioactivity and the corrosion resistance of the material.
Determination and speciation of tellurium in environmental samples using hydride generation atomic fluorescence spectroscopy (HG-AFS)
(Laurentian University of Sudbury, 2014-01-27) Alzahrani, Ali
This thesis focuses on developing a new method to measure trace tellurium (Te) in different environmental samples such as lake waters, mine tailings and sediments. The developed technique is based on Hydride Generation Atomic Fluorescence Spectroscopy (HG-AFS), a technique that can measure low concentration of Te and also allows for Te speciation at low cost and high efficiency in various environmental samples. To validate the method that could be used to determine Te speciation in various types of environmental samples, a series of tests has been designed for finding the best conditions to measure Te(IV) using HG-AFS and obtain accurate and reliable results. Those tests include the stability of the signal, the acidity of the solution, the volatility of Te after digestion of solids, the reduction from Te(VI) to Te(IV), the detection limit of the technique, and the validity of two digestion methods under the optimum (HG-AFS) instrumental settings. An interference study including the most common elements in the Earth’s crust such as (Ni, Fe, Pb, Cr, Cu, Co, Zn, Mn and Mo) was also performed. The results of this study showed that Cu(II) can severely interfere with Te quantification decreasing the Te signal to almost zero. Therefore, different masking agents such as 8-hydroxyquinoline, 1,10-phenanthroline, urea and thiourea were tested to reduce and eliminate this interference.
Determining the metabolic profiles in drosophila melanogaster: development and application of a novel ion-pairing liquid chromatography-mass spectrometry protocol
(Laurentian University of Sudbury, 2014-03-17) Knee, Jose
Genetic perturbations and foreign chemicals can result in a multitude of changes across a wide range of biochemical processes in a biological system. These perturbations may affect the metabolome, the small molecule metabolites in an organism. Recently, liquid-chromatography coupled to mass spectrometry (LC-MS) technology has been used to quantify large proportions of the metabolome, however standardized protocols are not yet available for use with Drosophila melanogaster. Here, I developed an ion-pairing LC-MS protocol for the metabolomic characterization of D. melanogaster and demonstrated its implementation in establishing the metabolomic profile of flies under oxidative stress and in the metabolic profiles of four different Drosophila species. I demonstrated that this new method allows for the detection of otherwise difficult metabolites and that it is repeatable and sensitive with acceptable levels of ionsuppression, matrix effects, limits of detection and quantification. I then used this method to determine and quantify the metabolomic fingerprints of loss of Superoxide dismutase activity and paraquat-induced stress. Comparing and contrasting the effects of these two sources of oxidative stress, I document both similarities and stressor-specific effects.
Development of a glycoliposomal delivery system to improve dynantin antagonism of the kappa opioid receptor
(2019-12-13) Boraman, Amanda
κ opioid receptors (KOP) play a role in the addictive properties of nicotine by opposing its rewarding effects. Using a KOP antagonist, we aim to modulate this relationship, and prevent the negative effects of withdrawal that causes individuals to relapse. A novel glycoliposomal delivery system was used to improve the stability of dynantin, a KOP antagonist peptide, in human plasma. Reverse phase high-performance liquid chromatography (RP-HPLC) was used to study the entrapment and stability of dynantin. Subsequently, the in vitro Parallel Receptor-ome Expression and Screening via Transcriptional Output–Transcriptional activation following arrestin translocation (PRESTO-TANGO) system was used to study the affinity and selectivity of dynantin at the KOP compared to the δ and μ opioid receptors (DOP and MOP). Results showed that dynantin had good selectivity for KOP without activating or blocking DOP or MOP. The ratio of peptide: mannose lipid: cholesterol was modified to improve the stability of dynantin in human plasma. Dynantin was completely degraded in plasma after 24 hours with no cholesterol present, while a 1:5:2 ratio (peptide: mannose lipid: cholesterol), had 71±4% of dynantin remaining after 24 hours. Importantly, the delivery system had no effect on the affinity of dynantin at the KOP. Our delivery system therefore shows promise in its ability to increase the bioavailability of therapeutic peptides such as dynantin, for which we demonstrate here a promising ability to act selectively as an antagonist at the KOP.
Diet-induced insulin resistance & exercise in Drosophila melanogaster is highly influenced by genotype & sex
(2020-11-03) Eng, Michelle
Type 2 Diabetes, characterized by a combination of insulin resistance and impaired insulin secretion, is a serious metabolic disorder in humans that not only affects adults, but now young children. The model organism Drosophila melanogaster has emerged as an excellent model to study metabolic regulation. Using a high sucrose diet to induce insulin resistance, I used multiple fly lines to explore how genotype and sex interacts with the progression of insulin resistance and how exercise can influence this response. Flies were grouped and placed on one of four conditions: control diet (CD), high sucrose diet (HSD), control diet with exercise (CDEx), or high sucrose diet with exercise (HSDEx). Flies were exercised using a fly treadmill. Weight and various metabolites known to respond to diet and exercise were quantified, along with gene expression of various nodes in the insulin pathway. Twenty-five percent of fly lines on the HSD displayed symptoms of insulin resistance, such as hyperglycemia, glucose intolerance, and/or hyperinsulinemia, as well as patterns in insulin pathway gene expression that is indicative of insulin resistance. Flies experienced physiological changes in response to exercise, which changed 11-13% of the metabolome of each sex, and 20-29% of the metabolome of each line. Strikingly, across all experiments, fly response to diet and exercise was highly genotype and sex-dependent. This study demonstrates the complex nature of insulin resistance and most importantly, the importance of studying disease related states using multiple genetic backgrounds and both sexes.
The effect of chemotherapy treatment on Ribosomal RNA integrity and ribosomal protein composition in ovarian cancer cells
(2017-06-01) Mispel-Beyer, Kyle
Recently we have demonstrated that several chemotherapy agents, of distinct mechanisms, promote highly reproducible ribosomal RNA (rRNA) degradation patterns, a phenomenon we call RNA disruption. These reproducible rRNA degradation bands have been observed in total RNA preparations from several cancer cell lines originating from various tissues. However, the effect of chemotherapeutic agents on ribosomal integrity and composition (including changes in rRNA and protein content) has not been examined. The purpose of the present study was to investigate the effect of docetaxel (DXL) chemotherapy treatment on ribosomal RNA and protein content in the A2780 ovarian carcinoma cell line. This involved isolation of ribosomes from untreated and DXL-treated A2780 cells using a differential centrifugation method. Differences in ribosomal RNA integrity and protein composition due to DXL treatment were determined using capillary gel electrophoresis (for rRNA), and 1D or 2D gel electrophoresis (for ribosomal proteins). Specific ribosomal proteins were detected by western blotting and quantified using densitometry. We report that DXL treatment of A2780 cells results in time-dependent degradation of rRNAs within isolated ribosomes, as well as changes in their relative protein composition. The DXL-induced changes in ribosome protein composition appeared to precede extensive rRNA degradation and were not observed in DXL-resistant A2780 cells.
Effect of doxorubicin and/or natural killer cells on RNA disruption in K562 chronic myeloid leukemia cells
(2020-09-22) Pascheto, Isabella
It has recently been observed that a variety of mechanistically distinct chemotherapy agents and cellular stressors induce ribosomal RNA (rRNA) degradation in tumour cells, a phenomenon termed RNA disruption. The RNA disruption assay (RDA) has been developed to quantify RNA disruption in a manner that can predict pathologic complete response and improved disease-free survival early in treatment. Immune checkpoint inhibitor (ICI) drugs are novel anti-cancer agents that can result in significant improvement in patient survival, but not all patients respond to these drugs. Thus, the RDA may be able to identify early in treatment ICI non-responders in order to avoid the continued costs and harmful side effects of this class of drugs and to consider alternate treatments. Since ICI drugs function by enhancing the efficacy of endogenous immune cells, this study assessed the ability of the RDA to quantify and monitor immune cell-mediated destruction of tumour cells in the absence or presence of the cytotoxic chemotherapy drug doxorubicin (DOX). This involved using the RDA to determine the RNA disruption index (RDI) for a particular sample via capillary gel electrophoresis and a proprietary algorithm. Loss of membrane integrity was also used to measure the cytotoxicity of immune cells towards tumour cells. In the K562 chronic myeloid leukemia cell line, RNA disruption was induced by a variety of chemotherapy agents, including DOX. Freshly isolated primary human natural killer (NK) cells also induced RNA disruption and loss of membrane integrity in K562 cells in a cell number-dependent manner. Pre-activation of NK cells with IL-2 augmented K562 cell RNA disruption and loss of membrane integrity in a dose-dependent manner. Preliminary studies suggested that pre-treatment with DOX may also augment NK cell-mediated RNA disruption in K562 cells. NK cell-mediated RNA disruption and loss of membrane integrity appear to correlate in a strong, positive manner in K562 cells. The pattern of rRNA degradation fragments induced by NK cells was very similar to that induced by chemotherapy agents. Taken together, these findings suggest that the RDA may have clinical utility in monitoring immune cell-mediated destruction of tumour cells induced by ICI therapies (prior to or after chemotherapy).
The effect of new drug exposure versus a drug free interval on prior drug resistance in ovarian cancer
(2016-06-16) Zhao, Yingxiao
Continuous exposure of ovarian tumours to a chemotherapy drug can result in the acquisition of drug resistance, which ultimately leads to chemotherapy failure and the death of a great majority of ovarian cancer patients. While previous studies suggest that withdrawal of the chemotherapy drug for a period of time (the drug-free interval) can result in restored clinical sensitivity to the drug, it is unclear whether exposure to a new drug of contrasting mechanism of action may accelerate restored sensitivity to the prior drug. In this study, we exposed a carboplatin-resistant ovarian tumour cell line (A2780CBN) to increasing concentrations of docetaxel (A2780CBNDXL cells) or we permitted the cells to grow in the absence of drug for an identical number of drug passages (A2780CBNCC cells). Similarly, we exposed a docetaxel-resistant ovarian tumour cell line (A2780DXL) to increasing concentrations of carboplatin (A2780DXLCBN cells) or we permitted the cells to growth in the absence of drug for an identical period (A2780DXLCC cells). By measuring the sensitivity of the above cell lines to either carboplatin or docetaxel, the aim of my thesis studies was to compare the effects of a drug-free interval or the acquisition of new drug resistance on prior drug resistance in vitro. The results showed that the prior carboplatin resistance was not significantly altered by the acquisition of docetaxel resistance or by withdrawal of carboplatin. However, prior docetaxel resistance was greatly reduced by selection for carboplatin resistance or by prolonged docetaxel withdrawal. Microarray analysis suggests that the loss of docetaxel resistance may be related to down-regulated expression of the ABCB1 and ABCB4 genes, which encode multidrug transporters. It may also relate to up-regulation of CYP1B1 gene expression, which encodes cytochrome P450, a phase I enzyme involved in taxane metabolism. The microarray analysis data also suggests that the newly established carboplatin resistance in A2780DXLCBN cells may be related to the expression of genes that promote cell survival by protecting cells from apoptotic death.
An EPR and DFT investigation of the products formed in the reaction of group 11 metal atoms with three-membered heterocyclic compounds
(2016-03-29) Orsini, Chad
Transition metals have been shown to be efficient catalysts in a variety of organic reactions. In particular, Group 11 metals have emerged as essential components in the carboxylation or metal-catalyzed ring expansion of three-membered heterocyclic compounds. Previous reports have speculated the presence of short-lived metal-substrate complexes and metallacyclic intermediates along the reaction path, yet to date there is no direct evidence for their existence. Using cryogenic matrix isolation EPR spectroscopy, we were able to characterize several highly reactive intermediates formed in the reactions of Group 11 metal atoms, Cu, Ag, and Au, with small, strained, heterocyclic compounds, namely, oxiranes, thiiranes, and aziridines. Experimental data indicates that the major products formed are mononuclear metal complexes, M-XCH2CH2 (X = O, S or NH). In addition, reaction mixtures containing Cu atoms and oxiranes or thiirane yield novel metallacycles, i.e., cupraoxetane and cuprathietane, respectively. DFT calculations were also used to support the structural assignments of the M-XCH2CH2 complexes.
Evaluation of liposomal bismuth-ethanedithiol-tobramycin for treatment of cystic fibrosis pulmonary pseudomonas aeruginosa infection
(Laurentian University of Sudbury, 2013-10-08) Alhariri, Moayad Abdulaziz I.
The effectiveness of liposomes incorporating bismuth-ethanedithiol and loaded with tobramycin (LipoBiEDT-TOB) at sub-inhibitory concentrations to inhibit the production of quorum sensing signaling molecules and virulence factors induced by P. aeruginosa was evaluated in vitro. In addition, we evaluated the efficacy and safety of free and encapsulated tobramycin in liposomal formulations administered intratracheally to rats chronically infected with P. aeruginosa. LipoBiEDT-TOB significantly reduced the production of quorum sensing signaling molecules and virulence factor secretion compared to free tobramycin. The LipoBiEDT-TOB formulation significantly reduced the bacterial count in lungs, modulated the IL-8 level in blood and minimized the nephrotoxicity that is associated with aminoglycoside treatment. These results support the hypothesis that aerosolization of liposomal aminoglycosides may enhance the management of chronic lung infections caused by resistant P. aeruginosa in patients with cystic fibrosis.
Examination of gene deletion as a mechanism of RBM5 downregulation in tobacco smoke-associated lung cancer
(2017-10-13) Hunt, Sarah C.
RBM5 is a tumour suppressor gene with substantially decreased expression in most lung cancers, especially in smokers, that may result from gene deletion. The objective of this study was to determine if significantly decreased levels of RBM5 expression in the lung cancers of smokers was related to RBM5 deletion. Using DNA from patient lung tissue, RBM5 gene copy number was quantified by quantitative polymerase chain reaction. Although deletions were detected in the lung specimens, RBM5 gene copy number was not significantly decreased in lung tumours. RBM5 deletions were detected in the non-tumour DNA of smokers, but not in the never-smokers, indicating that RBM5 gene deletion might be related to smoking. In conclusion, it appeared as though RBM5 was downregulated by more than one mechanism, which included gene deletion. Further analyses must be carried out to examine other mechanisms by which RBM5 is downregulated.
Examining the distribution of ketamine and metabolites in decomposed skeletal tissues: development of a high throughput approach and application to an environmental and decomposition study
(Laurentian University of Sudbury, 2014-08-07) Cornthwaite, Heather
The use of skeletal tissues in forensic toxicology research has increased dramatically in the last 5 years. These studies have yielded valuable information pertinent to using skeletal tissues as a biological matrix in drug analysis. The majority of these studies have been completed on a small scale so a larger scale is needed for further research. Here, a high throughput microwave assisted extraction (MAE) and microplate solid phase extraction (MPSPE) protocol is developed and implemented to examine how body position and microclimate affect ketamine and metabolite distribution in decomposed skeletal tissue. Analytes were successful recovered in 30 min following MAE compared to 180 min for passive solvent extraction (PSE). Body proved to be significantly different in the observed drug levels at both microclimates. The sunlit microclimate had significantly higher drug levels, with less maggot activity, compared to the shaded microclimate.
Fate of limestone dissolution products in acidic metalcontaminated soil mesocosms
(Laurentian University of Sudbury, 2014-03-17) Driscoll, Kendra
The impact of liming (10 t ha-1 of calcitic and dolomitic limestone, separately) on the soil solution and soil matrix was investigated in an acidic metal-contaminated soil from Sudbury, ON. A soil mesocosm experiment was performed; columns were leached with simulated rainwater and the soil solution collected at various locations throughout the soil column. The dissolution rate of calcitic limestone used for this experiment was found to be approximately double that of the dolomitic limestone investigated. Calcium and Mg released during limestone dissolution migrated through the soil profile to the Bf-BC interface. The addition of limestone increased the pH and decreases the bioavailability of Ni, Cu, Co, Cd, As, Ba, Mn, and Zn the LFH horizon. Amending acid, contaminated soils with calcitic or dolomitic limestone has profound effects on soil solution chemistry.
Formulation and efficacy of liposome-encapsulated azithromycin for pulmonary infection due to Pseudomonias Aeruginosa
(2016-05-02) Solleti, Venkata Saran Tejaswi
Cystic fibrosis is the most common life-threatening autosomal recessive disorder in Caucasians. Recurrent pulmonary infection and inflammation are the major risk factors associated with cystic fibrosis. Microbial infection with highly resistant pathogens such as Burkholderia cenocepacia and Pseudomonas aeruginosa, is principally associated with cystic fibrosis. The effective management of pulmonary infection in cystic fibrosis patients is not controllable due to the multidrug-resistant strains and potential side effects of antibiotics usage. Liposomal encapsulation of macrolide antibiotics such as azithromycin show increased drug concentrations at the site of infection, along with reduced toxic effects. In this thesis work, liposome-loaded azithromycin formulation was prepared by dehydration-rehydration vesicle method and related characterizations including cytotoxicity were identified. The effects of liposomal azithromycin on biofilm community, purified bacterial virulence factors were determined and motility studies were performed in clinical isolate of P. aeruginosa. We found that liposomal azithromycin reduced biofilm activity, virulence factors production and bacterial motility. The liposomal formulation confirmed interactions between liposomes and bacterial membranes besides insignificant hemolysis or A549 cell toxicity. The end results collectively indicate that liposomal drug delivery systems could be a promising model to enhance the efficacy of antibiotics against resistant bacterial strains in lung infections.
A generalized electronic diabatic model applied to two-state reactions.
(Laurentian University of Sudbury, 2015-01-27) Laverdure, Laura Bray
A generalized electronic diabatic model for chemical reactions includes a physical mechanism for the transition from a reactant-like to a product-like quantum state, namely, an external field. In our model, an external electric field couples states and modifies effective potential energy surfaces thereby allowing to treat a reaction as a fully quantum process. Through semi-classical models of two-state reactions, we show that we can control the identity of the most stable nuclear configuration by varying the form and intensity of the external field’s coupling potential. We group topologically equivalent potential energy curves in phase diagrams for a manifold of simple two-state models. We also illustrate the method’s implementation in a fully quantum-mechanical approach by considering two diabatic states in the radical HBN⇄BNH isomerization. To ensure diabaticity, these states are built on a grid of floating Gaussian orbitals and the potential energy curves are constructed by moving the nuclei.

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