Free radicals are connected to oxidative stress that results in aging, cancer, Parkinson's, Alzheimer's, and Sickle Cell Disease, among many other health problems. Indirect methods, such as spin trapping, are commonly used to circumvent the difficulty of direct experimental observation and identification of short-lived free radicals. Spin trapping stabilizes and lengthens the lifetime of the radical through reaction with another molecule so that it is detectable by Electron Paramagnetic Resonance spectroscopy. Recent efforts have been directed towards in vivo spin trapping. However, the most common nitroso and nitrone spin traps are known to be toxic at high concentrations. Further complicating the interpretation of the experimental results to establish the reaction mechanisms is that the superoxide adduct of the spin trap enzymatically degrades and decays into that of the hydroxyl adduct. Melatonin is a relatively nontoxic natural antioxidant that is directly reactive towards the hydroxyl radical and relatively unreactive towards the superoxide radical. While melatonin as an antioxidant has been experimentally well studied, its reaction mechanisms are still not well understood. This work focuses on computational quantum chemistry studies of proposed reaction mechanisms in the gas phase for direct oxidation of melatonin. Geometry optimizations are performed using Hartree-Fock (HF) and Density Functional Theory (DFT) methods in conjunction with Dunning's correlation-consistent polarized valence-only triple zeta (cc-pVTZ) basis set. Single point energies were calculated using second-order Møller-Plesset perturbation theory (MP2) in conjunction with cc-pVDZ, cc-pVTZ, and cc-pVQZ basis sets. Stable structures and conformations of melatonin radical intermediates will help understand how melatonin functions as an antioxidant and determine if a melatonin derivative could function as a possible in vivo spin trap.
The effects of new heteroaryl (thiadiazoyl and furoxanyl) substituents on a parent nitrone spin trap have been computationally studied using ab initio methods at the HF and MP2 levels with the 6-31G(d), cc-pVDZ and cc-pVTZ basis sets. The calculations show that new heteroaryl nitrones are very reactive, with thiadiazoyl substituted-nitrones being the most reactive spin traps and 1,2,4 -thiadiazol -5-yl nitrone is the most polar spin trap. Additionally, the thermodynamics of the spin trapping of new heteroaryl nitrones at C-site and O-site with the biologically relevant radicals (·H, ·CH3 and ·OH) has been studied using HF/6-31G(d). The calculations show that, thermodynamically, the spin trapping of furoxan-3-yl nitrone with ·H, ·CH3 and ·OH radicals gives the most stable spin adducts at the C site while furoxan-4-yl nitrone with these radicals gives the most stable spin adducts at the O site. However, the spin trapping at the C site of new heteroaryl nitrones is highly exothermic as compared to the O site of the nitrone, with no activation energy barrier for any of the radicals studied. Finally, the thermodynamics of the spin trapping of DMPO, PBN and FxBN with ·OH radical has also been studied using DFT with M06/6-31*. The spin trapping of FxBN with ·OH is thermodynamically favored over the spin trapping of DMPO and PBN with ·OH. The double spin adduct of FxBN with ·OH radical is thermodynamically favored over the monoadduct of FxBN with ·OH radical.
This research aimes to calculate the reaction rate constants for the reaction of 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and 2-ethoxycarbonyl-2-methyl-3,4-dihydro-2H-pyrrole-l-oxide (EMPO) with the hydroxyl radical ·OH) using chemically accurate energies (errors ~1kcal/mol or less) using composite quantum chemistry methods. DMPO and EMPO spin traps are commonly used to study radical reactions in biological systems and have been the focus of much computational and experimental research, but accurate rate constants have not been previously obtained using computational methods. On the route to obtaining chemically accurate energies, the complete basis set limit for HF and MP2 energies were calculated using the density functional theory optimized geometry.
Dirhodium complexes such as carboxylates and carboxylamidates are very efficient metal catalysts used in the synthesis of pharmaceuticals and agrochemicals. Recent experimental work in Dr. Cassandra Eagle's research group has indicated that there are significant differences in the isomeric ratios obtained among the possible products when synthesizing these complexes and that the crystal structures exhibit anomalous bond angles for the rhodium-ligand bond. The relative stabilities and lowest energy geometries of several dirhodium carboxylates and carboxylamidates with nitrile ligands are being calculated using NWChem at the HF/LANL2DZ ECP, {6-31G, cc-pVDZ, cc-pVTZ} and DFT/B3LYP/LANL2DZ ECP, {6-31G, cc-pVDZ, cc-pVTZ} levels of theory. The LANL2DZ ECP (effective core potential) basis set was used for the rhodium atoms and the 6-31G, cc-pVDZ, or cc-pVTZ basis set was used for all other atoms. The optimized structures are consistent with the crystallographic results and the experimental isomer distribution. Examination of the energies of the molecular orbitals that have previously be described as involved in form a p-back bond between to rhodium and the ligand are too separated in energy and show no evidence of forming a p-back bond. Thus the p -back bonding model is incomplete or even insufficient to explain the bent rhodium-ligand bond angles. This merits additional investigation to elucidate the details of the rhodium-ligand bond and, if successful, may provide additional insight in the catalytic properties of these complexes.
The cyclic nitrone 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), and the lesser known linear phenyl-N-tert-butylnitrone (PBN) and its phosphorylated analogues have been used as spin traps for the investigation of free radicals in biological systems. Not surprisingly, the theoretical work on these molecules suggests that there are important differences in their properties between biological systems and isolated molecules in the gas phase, most likely resulting from intra and intermolecular hydrogen bonding. Most dielectric solvation models, such as the polarized continuum model and COSMO, are incapable of direct determination of solvent-spin trap chemical interactions. Hybrid models incorporating COSMO for long range effects and discrete solvent molecules for short range effects, at the DFT/B3LYP/6-31G* level of theory, are being used to study the stabilization and alteration of the spin trap molecules properties in protic and aprotic polar solvents.
Fungal infections, caused by Candida species have increased significantly over the last two decades. It is one of the most prevalent fungal infections in immunocompromised, elderly, and intensive care unit patients. C. albicans is a polymorphic fungus, which can grow as unicellular budding yeast cells or as filamentous hyphae. How the human immune system discriminates between yeast and hyphae is not known, but preliminary data indicate that hyphal cell wall glucan plays an important role. We have acquired preliminary experimental data that indicate that C. albicans hyphal glucan contains additional structures that have never been previously identified and that are unique to hyphal glucan. Specifically, C. albicans hyphal glucan lacks reducing and non-reducing termini, indicating that this glucan has a “closed chain” or cyclic structure. This glucan also has previously unknown side-chain linkages. Given the limited experimental structural data currently available, molecular modeling is required to establish the tertiary structure of hyphal glucan. HF and DFT structural calculations are being performed to develop a conceptual model of the tertiary structure.