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Computation of Molecular Properties at the Ab Initio LimitTemelso, Berhane 16 January 2007 (has links)
The accuracy of a quantum chemical calculation inherently depends on the ability to account for the completeness of the one- and n-particle spaces. The size of the basis set used can be systematically increased until it reaches the complete one-particle basis set limit (CBS) while the n-particle space approaches its exact full configuration interaction (FCI) limit by following a hierarchy of electron correlation methods developed over the last seventy years. If extremely high accuracy is desired, properly correcting for very small effects such as those resulting the Born-Oppenheimer approximation and the neglect of relativistic effects becomes indispensable. For a series of chemically interesting and challenging systems, we identify the limits of conventional approaches and use state-of-the-art quantum chemical methods along with large basis sets to get the “right answer for the right reasons.” First, we quantify the importance of small effects that are ignored in conventional quantum chemical calculations and manage to achieve spectroscopic accuracy (agreement of 1 cm−1 or less with experimental harmonic vibrational frequencies) for BH, CH+ and NH. We then definitively resolve the global minimum structure for Li₆ , Li₆⁺ , and Li₆- using high accuracy calculations of the binding energies, ionization potentials, electron affinities and vertical excitation spectra for the competing isomers. The same rigorous approach is used to study a series of hydrogen transfer reactions and validate the necessary parameters for the hydrogen abstraction and donation steps in the mechanosynthesis of diamondoids. Finally, in an effort to overcome the steep computational scaling of most high-level methods, a new hybrid methodology which scales as O(N⁵) but performs comparably to O(N⁶) methods is benchmarked for its performance in the equilibrium and dissociation regimes.
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Therapeutic Antibody Against Neisseria gonorrhoeae Lipooligosaccharide, a Phase-variable Virulence FactorChakraborti, Srinjoy 25 May 2017 (has links)
Neisseria gonorrhoeae (Ng) which causes gonorrhea has become multidrug-resistant, necessitating the development of novel therapeutics and vaccines. mAb 2C7 which targets an epitope within an important virulence factor, the lipooligosaccharide (LOS), is a candidate therapeutic mAb. Ninety-four percent of clinical isolates express the 2C7-epitope which is also a vaccine target.
Ng expresses multiple LOS(s) due to phase-variation (pv) of LOS glycosyltransferase (lgt) genes. mAb 2C7 reactivity requires a lactose extension from the LOS core Heptose (Hep) II (i.e. lgtG ‘ON’ [G+]). Pv results in HepI with: two (2-), three (3-), four (4-), or five (5-) hexoses (Hex). How HepI glycans impact Ng infectivity and mAb 2C7 function are unknown and form the bases of this dissertation.
Using isogenic mutants, I demonstrate that HepI LOS glycans modulate mAb 2C7 binding. mAb 2C7 causes complement (C’)-dependent bacteriolysis of three (2-Hex/G+, 4-Hex/G+, and 5-Hex/G+) of the HepI mutants in vitro. The 3-Hex/G+ mutant (resistant to C’-dependent bacteriolysis) is killed by neutrophils in the presence of mAb and C’. In mice, 2- and 3-Hex/G+ infections are significantly shorter than 4- and 5-Hex/G+ infections. A chimeric mAb 2C7 that hyperactivates C’, attenuates only 4- and 5-Hex/G+ infections.
This study enhances understanding of the role of HepI LOS pv in gonococcal infections and shows that longer HepI glycans are necessary for prolonged infections in vivo. This is the first study that predicts in vitro efficacy of mAb 2C7 against all four targetable HepI glycans thereby strengthening the rationale for development of 2C7-epitope based vaccines and therapeutics.
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