@phdthesis{Paasche2013,
  author    = {Paasche, Alexander},
  title     = {Mechanistic Insights into SARS Coronavirus Main Protease by Computational Chemistry Methods},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-79029},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2013},
  abstract  = {The SARS virus is the etiological agent of the severe acute respiratory syndrome, a deadly disease that caused more than 700 causalities in 2003. One of its viral proteins, the SARS coronavirus main protease, is considered as a potential drug target and represents an important model system for other coronaviruses. Despite extensive knowledge about this enzyme, it still lacks an effective anti-viral drug. Furthermore, it possesses some unusual features related to its active-site region. This work gives atomistic insights into the SARS coronavirus main protease and tries to reveal mechanistic aspects that control catalysis and inhibition. Thereby, it applies state-of-the-art computational methods to develop models for this enzyme that are capable to reproduce and interpreting the experimental observations. The theoretical investigations are elaborated over four main fields that assess the accuracy of the used methods, and employ them to understand the function of the active-site region, the inhibition mechanism, and the ligand binding. The testing of different quantum chemical methods reveals that their performance depends partly on the employed model. This can be a gas phase description, a continuum solvent model, or a hybrid QM/MM approach. The latter represents the preferred method for the atomistic modeling of biochemical reactions. A benchmarking uncovers some serious problems for semi-empirical methods when applied in proton transfer reactions. To understand substrate cleavage and inhibition of SARS coronavirus main protease, proton transfer reactions between the Cys/His catalytic dyad are calculated. Results show that the switching between neutral and zwitterionic state plays a central role for both mechanisms. It is demonstrated that this electrostatic trigger is remarkably influenced by substrate binding. Whereas the occupation of the active-site by the substrate leads to a fostered zwitterion formation, the inhibitor binding does not mimic this effect for the employed example. The underlying reason is related to the coverage of the active-site by the ligand, which gives new implications for rational improvements of inhibitors. More detailed insights into reversible and irreversible inhibition are derived from in silico screenings for the class of Michael acceptors that follow a conjugated addition reaction. From the comparison of several substitution patterns it becomes obvious that different inhibitor warheads follow different mechanisms. Nevertheless, the initial formation of a zwitterionic catalytic dyad is found as a common precondition for all inhibition reactions. Finally, non-covalent inhibitor binding is investigated for the case of SARS coranavirus main protease in complex with the inhibitor TS174. A novel workflow is developed that includes an interplay between theory and experiment in terms of molecular dynamic simulation, tabu search, and X-ray structure refinement. The results show that inhibitor binding is possible for multiple poses and stereoisomers of TS174.},
  subject      = {SARS},
  language  = {en}
}
@phdthesis{Schaumloeffel2014,
  author    = {Schauml{\"o}ffel, Anu Lena},
  title     = {Quantenchemische Studien der Chiroptischen Eigenschaften ausgedehnter π-Systeme sowie Beitr{\"a}ge zu SpecDis},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-108291},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {F{\"u}r die Aufkl{\"a}rung der absoluten Stereostruktur von chiralen Molek{\"u}len, die ein Chromophorsystem besitzen, hat sich die Kombination der experimentellen und theoretischen Spektroskopie des elektronischen Circulardichroismus (ECD) als Methode bew{\"a}hrt. In der vorliegenden Arbeit wurden die chiroptischen Eigenschaften von Bisbibenzyl-Makrocyclen, Mono- und Bis(cycloketo)porphyrinen, der Mohnbl{\"u}tenpigmente Nudicaulin I und II sowie von Bordipyrrol-Dimeren mit quantenchemischen Methoden untersucht. Zu diesem Zweck wurden verschiedene dichtefunktionaltheoretische (DFT) Ans{\"a}tze und post-HF-Methoden, wie z. B. der Coupled-Cluster-Ansatz RI-CC2, bez{\"u}glich ihrer Eignung, die Grund- und angeregten Zust{\"a}nde (UV/vis- und ECD-Eigenschaften) der einzelnen Verbindungen korrekt wiederzugeben, evaluiert. Da bei quantenchemischen UV- und ECD-Rechnungen an ausgedehnten π-Systemen aufgrund energetisch nah beieinander liegender Anregungen die Wahrscheinlichkeit f{\"u}r ghost states und charge-transfer-{\"U}berg{\"a}nge sowie Multireferenz-Problematiken steigt, wurden diese Aspekte genauer betrachtet. Die ersten zwei Ph{\"a}nomene lassen sich bereits auf TD-DFT-Niveau durch genaue Analyse der theoretischen spektroskopischen Daten ermitteln und unter Umst{\"a}nden durch entsprechend korrigierte Funktionale sogar sehr gut beschreiben. Im Gegensatz dazu k{\"o}nnen Doppelanregungsanteile {\"u}berhaupt erst durch Rechnungen mit geeigneten Methoden, wie z. B. das hier verwendete SORCI-Verfahren, erfasst werden. Zus{\"a}tzlich wurde das zur Auswertung von UV und ECD-Daten entwickelte Programm SpecDis um Funktionalit{\"a}ten erweitert, welche die Berechnung des {\"U}bereinstimmungsgrades zweier UV- bzw. ECD-Kurven erm{\"o}glichen, und dadurch ein zus{\"a}tzliches quantitatives Kriterium f{\"u}r die Verl{\"a}sslichkeit des Spektrenvergleichs und folglich f{\"u}r die Zuordnung der absoluten Konfiguration bieten.},
  subject      = {Chiralit{\"a}t <Chemie>},
  language  = {de}
}