Für die Aufklärung der absoluten Stereostruktur von chiralen Molekülen, die ein Chromophorsystem besitzen, hat sich die Kombination der experimentellen und theoretischen Spektroskopie des elektronischen Circulardichroismus (ECD) als Methode bewährt. In der vorliegenden Arbeit wurden die chiroptischen Eigenschaften von Bisbibenzyl-Makrocyclen, Mono- und Bis(cycloketo)porphyrinen, der Mohnblütenpigmente Nudicaulin I und II sowie von Bordipyrrol-Dimeren mit quantenchemischen Methoden untersucht. Zu diesem Zweck wurden verschiedene dichtefunktionaltheoretische (DFT) Ansätze und post-HF-Methoden, wie z. B. der Coupled-Cluster-Ansatz RI-CC2, bezüglich ihrer Eignung, die Grund- und angeregten Zustände (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 für ghost states und charge-transfer-Übergänge sowie Multireferenz-Problematiken steigt, wurden diese Aspekte genauer betrachtet. Die ersten zwei Phänomene lassen sich bereits auf TD-DFT-Niveau durch genaue Analyse der theoretischen spektroskopischen Daten ermitteln und unter Umständen durch entsprechend korrigierte Funktionale sogar sehr gut beschreiben. Im Gegensatz dazu können Doppelanregungsanteile überhaupt erst durch Rechnungen mit geeigneten Methoden, wie z. B. das hier verwendete SORCI-Verfahren, erfasst werden. Zusätzlich wurde das zur Auswertung von UV und ECD-Daten entwickelte Programm SpecDis um Funktionalitäten erweitert, welche die Berechnung des Übereinstimmungsgrades zweier UV- bzw. ECD-Kurven ermöglichen, und dadurch ein zusätzliches quantitatives Kriterium für die Verlässlichkeit des Spektrenvergleichs und folglich für die Zuordnung der absoluten Konfiguration bieten. / For the elucidation of the absolute stereostructure of chiral molecules possessing a chromophore, the combination of experimental and theoretical spectroscopy of the electronic circular dichroism (ECD) has proven a valuable tool. In the present work, the chiroptical properties of bisbibenzyl macrocycles, mono- and bis(cycloketo)porphyrins, the poppy-petal pigments nudicaulins I and II, and boron-dipyrrole dimers were investigated with quantum-chemical methods. For this purpose, different density-functional and post-HF methods, for example the coupled-cluster approach RI-CC2, were evaluated regarding their suitability to correctly describe the ground and exited states (UV/vis and ECD properties) of each compound. Since the probability of ghost states, charge-transfer transitions, and multi-reference problems increases for quantum-chemical UV and CD calculations of extended π systems due to energetically close-lying excitations, these aspects were closely examined. The first two phenomena can be detected on TD-DFT level of theory by a thorough analysis of the theoretical spectroscopic data, and can in some cases even be described quite well by specially corrected functionals. By contrast, double excitations can only be included in the calculations by using suitable methods, e.g. the herein used SORCI approach. Additionally, functionalities were added to the program SpecDis which allow for the calculation of the degree of similarity of either two UV or ECD curves, and thus, offer an additional quantitative measure for the comparison of spectra and, in consequence, for the reliability of the assignment of an absolute configuration.

Unrestricted Kohn-Sham (broken symmetry) density functional calculations have been used to determine the low-energy geometries of the chromium dihalide molecules (CrX2) and their clusters, Cr2X4, Cr3X6, and Cr4X8. The monomers are also investigated at a higher level, including coupled-cluster and state-average CASSCF computations. Our calculations show that the monomers have a 5B2 ground state arising from the Renner-Teller distorted 5IIg transition state, leading to a bent geometry. The global minima of the gas-phase clusters of CrF2 and CrCl2 consist of two-dimensional, anti-ferromagnetically coupled chains of CrX2 units forming four-membered, doubly bridged Cr2X2 rings, closely resembling their solid-state structures. The global minima of the CrBr2 and CrI2 clusters consist of the same two-dimensional chain-like structures for their dimers, but their trimers and tetramers consist of three-dimensional ’triangular’ structures which contain two capping ligands bound to three chromium atoms along with a Cr-Cr bond. Each Cr atom within these clusters has spin quantum number S=2. There is approximately a constant change in energy, between 45-55 kcal/mol, with every new CrX2 unit during cluster formation. Information about the structure of the CrCl2 clusters is used in the reanalysis of high-temperature electron diffraction data. The vapor at 1170 K contains about 77% monomeric molecules, 19% dimers, and a small amount of trimers. Monomeric CrCl2 is found to be bent with a bond angle of 149(10)degrees, in good agreement with our computations. Solid-state DFT calculations are performed on alpha-CrCl2 to determine the lattice structure and spin-coupling constants for the Cr atoms within the crystals. The GGA (PW91) method produces a structure in good agreement with the literature. In the lowest energy structure, the spins of the Cr atoms within the chains along the crystallographic c-axis are anti-ferromagnetically coupled with four parallel spins situated almost exclusively in the d-bands of Cr along these chains. This anti-ferromagnetic coupling is also seen in the CrX2 clusters.

Unrestricted Kohn-Sham (broken symmetry) density functional calculations have been used to determine the low-energy geometries of the chromium dihalide molecules (CrX2) and their clusters, Cr2X4, Cr3X6, and Cr4X8. The monomers are also investigated at a higher level, including coupled-cluster and state-average CASSCF computations. Our calculations show that the monomers have a 5B2 ground state arising from the Renner-Teller distorted 5IIg transition state, leading to a bent geometry. The global minima of the gas-phase clusters of CrF2 and CrCl2 consist of two-dimensional, anti-ferromagnetically coupled chains of CrX2 units forming four-membered, doubly bridged Cr2X2 rings, closely resembling their solid-state structures. The global minima of the CrBr2 and CrI2 clusters consist of the same two-dimensional chain-like structures for their dimers, but their trimers and tetramers consist of three-dimensional ’triangular’ structures which contain two capping ligands bound to three chromium atoms along with a Cr-Cr bond. Each Cr atom within these clusters has spin quantum number S=2. There is approximately a constant change in energy, between 45-55 kcal/mol, with every new CrX2 unit during cluster formation. Information about the structure of the CrCl2 clusters is used in the reanalysis of high-temperature electron diffraction data. The vapor at 1170 K contains about 77% monomeric molecules, 19% dimers, and a small amount of trimers. Monomeric CrCl2 is found to be bent with a bond angle of 149(10)degrees, in good agreement with our computations. Solid-state DFT calculations are performed on alpha-CrCl2 to determine the lattice structure and spin-coupling constants for the Cr atoms within the crystals. The GGA (PW91) method produces a structure in good agreement with the literature. In the lowest energy structure, the spins of the Cr atoms within the chains along the crystallographic c-axis are anti-ferromagnetically coupled with four parallel spins situated almost exclusively in the d-bands of Cr along these chains. This anti-ferromagnetic coupling is also seen in the CrX2 clusters.

Unrestricted Kohn-Sham (broken symmetry) density functional calculations have been used to determine the low-energy geometries of the chromium dihalide molecules (CrX2) and their clusters, Cr2X4, Cr3X6, and Cr4X8. The monomers are also investigated at a higher level, including coupled-cluster and state-average CASSCF computations. Our calculations show that the monomers have a 5B2 ground state arising from the Renner-Teller distorted 5IIg transition state, leading to a bent geometry. The global minima of the gas-phase clusters of CrF2 and CrCl2 consist of two-dimensional, anti-ferromagnetically coupled chains of CrX2 units forming four-membered, doubly bridged Cr2X2 rings, closely resembling their solid-state structures. The global minima of the CrBr2 and CrI2 clusters consist of the same two-dimensional chain-like structures for their dimers, but their trimers and tetramers consist of three-dimensional ’triangular’ structures which contain two capping ligands bound to three chromium atoms along with a Cr-Cr bond. Each Cr atom within these clusters has spin quantum number S=2. There is approximately a constant change in energy, between 45-55 kcal/mol, with every new CrX2 unit during cluster formation. Information about the structure of the CrCl2 clusters is used in the reanalysis of high-temperature electron diffraction data. The vapor at 1170 K contains about 77% monomeric molecules, 19% dimers, and a small amount of trimers. Monomeric CrCl2 is found to be bent with a bond angle of 149(10)degrees, in good agreement with our computations. Solid-state DFT calculations are performed on alpha-CrCl2 to determine the lattice structure and spin-coupling constants for the Cr atoms within the crystals. The GGA (PW91) method produces a structure in good agreement with the literature. In the lowest energy structure, the spins of the Cr atoms within the chains along the crystallographic c-axis are anti-ferromagnetically coupled with four parallel spins situated almost exclusively in the d-bands of Cr along these chains. This anti-ferromagnetic coupling is also seen in the CrX2 clusters.

The Diels-Alder reaction is one of the most powerful synthetic tools in organic chemistry, and asymmetric Diels-Alder catalysis allows for rapid construction of chiral carbon scaffolds. For this reason, considerable effort has been invested in developing efficient and stereoselective organo- and biocatalysts. However, Diels-Alder is a virtually unknown reaction in Nature, and to engineer an enzyme into a Diels-Alderase is therefore a challenging task. Despite several successful designs of catalytic antibodies since the 1980’s, their catalytic activities have remained low, and no true artificial ’Diels-Alderase’ enzyme was reported before 2010. In this thesis, we employ state-of-the-art computational tools to study the mechanism of organocatalyzed Diels-Alder in detail, and to redesign existing enzymes into intermolecular Diels-Alder catalysts. Papers I–IV explore the mechanistic variations when employing increasingly activated reactants and the effect of catalysis. In particular, the relation between the traditionally presumed concerted mechanism and a stepwise pathway, forming one bond at a time, is probed. Papers V–X deal with enzyme design and the computational aspects of predicting catalytic activity. Four novel, computationally designed Diels-Alderase candidates are presented in Papers VI–IX. In Paper X, a new parameterization of the Linear Interaction Energy model for predicting protein-ligand affinities is presented. A general finding in this thesis is that it is difficult to attain large transition state stabilization effects solely by hydrogen bond catalysis. In addition, water (the preferred solvent of enzymes) is well-known for catalyzing Diels- Alder by itself. Therefore, an efficient Diels-Alderase must rely on large binding affinities for the two substrates and preferential binding conformations close to the transition state geometry. In Papers VI–VIII, we co-designed the enzyme active site and substrates in order to achieve the best possible complementarity and maximize binding affinity and pre-organization. Even so, catalysis is limited by the maximum possible stabilization offered by hydrogen bonds, and by the inherently large energy barrier associated with the [4+2] cycloaddition. The stepwise Diels-Alder pathway, proceeding via a zwitterionic intermediate, may offer a productive alternative for enzyme catalysis, since an enzyme active site may be more differentiated towards stabilizing the high-energy states than for the standard mechanism. In Papers I and III, it is demonstrated that a hydrogen bond donor catalyst provides more stabilization of transition states having pronounced charge-transfer character, which shifts the preference towards a stepwise mechanism. Another alternative, explored in Paper IX, is to use an α,β -unsaturated ketone as a ’pro-diene’, and let the enzyme generate the diene in situ by general acid/base catalysis. The results show that the potential reduction in the reaction barrier with such a mechanism is much larger than for conventional Diels-Alder. Moreover, an acid/base-mediated pathway is a better mimic of how natural enzymes function, since remarkably few catalyze their reactions solely by non-covalent interactions. / <p>QC 20120903</p>

This dissertation thesis consists of a series of chapters that are interwoven by solving interesting biological problems, employing various computational methodologies. These techniques provide meaningful physical insights to promote the scientific fields of interest. Focus of chapter 1 concerns, the importance of computational tools like docking studies in advancing structure based drug design processes. This chapter also addresses the prime concerns like scoring functions, sampling algorithms and flexible docking studies that hamper the docking successes. Information about the different kinds of flexible dockings in terms of accuracy, time limitations and success studies are presented. Later the importance of Induced fit docking studies was explained in comparison to traditional MD simulations to predict the absolute binding modes. Chapter 2 and 3 focuses on understanding, how sickle cell disease progresses through the production of sickled hemoglobin and its effects on sickle cell patients. And how, hydroxyurea, the only FDA approved treatment of sickle cell disease acts to subside sickle cell effects. It is believed the primary mechanism of action is associated with the pharmacological elevation of nitric oxide in the blood, however, the exact details of this mechanism is still unclear. HU interacts with oxy and deoxyHb resulting in slow NO production rates. However, this did not correlate with the observed increase of NO concentrations in patients undergoing HU therapy. The discrepancy can be attributed to the interaction of HU competing with other heme based enzymes such as catalase and peroxidases. In these two chapters, we investigate the atomic level details of this process using a combination of flexible-ligand / flexible-receptor virtual screening (i.e. induced fit docking, IFD) coupled with energetic analysis that decomposes interaction energies at the atomic level. Using these tools we were able to elucidate the previously unknown substrate binding modes of a series of hydroxyurea analogs to human hemoglobin, catalase and the concomitant structural changes of the enzymes. Our results are consistent with kinetic and EPR measurements of hydroxyurea-hemoglobin reactions and a full mechanism is proposed that offers new insights into possibly improving substrate binding and/or reactivity. Finally in chapter 4, we have developed a 3D bioactive structure of O6-alkylguanine-DNA alkyltransferase (AGT), a DNA repair protein using Monte Carlo conformational search process. It is known that AGT prevents DNA damage, mutations and apoptosis arising from alkylated guanines. Various Benzyl guanine analouges of O6- methylguanine were tested for activity as potential inhibitors. The nature and position of the substitutions methyl and aminomethyl profoundly affected their activity. Molecular modeling of their interactions with alkyltransferase provided a molecular explanation for these results. The square of the correlation coefficient (R2 ) obtained between E-model scores (obtained from GLIDE XP/QPLD docking calculations) vs log(ED)values via a linear regression analysis was 0.96. The models indicate that the ortho-substitution causes a steric clash interfering with binding, whereas the meta-aminomethyl substitution allows an interaction of the amino group to generate an additional hydrogen bond with the protein. Using this model for virtually screening studies resulted in identification of seven lead compounds with novel scaffolds from National Cancer Institute Diversity Set2.

←Within this dissertation the topic of virtual screening is discussed with regard to three different cancer targets and also a brief introduction of the tools used in virtual screening. In Chapter 1, the reader will be introduced to virtual screening and the programs that are used in virtual screening. In Chapter 2, the first of three projects are discussed. This project consists of the work that was done to find inhibitors of the P53 binding domain of MDMX. In this project the mobility of residues within the binding site of MDMX are discussed and the ways in which we attempted to model how drugs would bind two adjacent pockets within MDMX. In Chapter 3, the virtual screening and modeling work done for RING domain of MDM2 and MDMX is discussed. This work was done in conjunction with Moffitt Cancer Center in order to solve the 60 year old mystery of the mechanism of how thalidomide and possibly its analog lenalidomide caused children to be born limbless. Current thinking is that Cereblon through an unknown teratogenic mechanism activates an increase in FGF8. We suggest a mechanism that may happen in parallel that involves stabilization of MDM2 and the reduction of P63 levels. Chapter 4, the work that was done against the BH3 binding domain of MCL-1 is discussed in conjunction with collaboration with the Manetsch lab. In order to complete this screening the validation of IC50 values and then attempt to modify those products based upon the structure of MCL-1. Chapter 5 discusses the work done to find inhibitors of deoxycytidine kinase. All of these chapters taken together provide a brief overview of the computational work done produce inhibitors of Protein-Protein Interaction against three major cancer targets.

Computational chemistry offers one the ability to develop a better understanding of the complex physical and chemical interactions that are fundamental to macro- and mesoscopic processes that are seen in laboratory experiments, industrial processes, and ordinary, everyday life. For many systems, the physics of interest occur at the molecular or atomistic levels, and in these cases, computational modeling and two well refined simulation techniques become invaluable: Monte Carlo (MC) and molecular dynamics (MD). In this work, two well established problems were tackled. First, models and potentials for various gas molecules were produced and refined from first principles. These models, although based on work done previously by Belof et al., are novel due to the inclusion of many-body van der Waals interactions, advanced r-12 repulsion combining rules for treating unlike intra- and intermolecular interactions, and highly-efficient treatment of induction interactions. Second, a multitude of models were developed and countless MD simulations were performed in order to describe and understand the giant frictional anisotropy of d-AlCoNi, first observed by Park et al. in 2005.

In the design of novel materials, tunable properties are parameters such as composition or structure that may be adjusted in order to enhance a desired chemical or material property. Trends in tunable properties can be accurately predicted using computational and combinatorial chemistry tools in order to optimize a desired property. I present a study of tunable properties in materials and employ a variety of algorithms that ranges from simple screening to machine learning. In the case of tuning a nanocomposite membrane for olefin/paraffin separations, I demonstrate a rational design approach based on statistical modeling followed by ab initio modeling of the interaction of olefins with various nanoparticles. My simplified model of gases diffusing on a heterogeneous lattice identifies the conditions necessary for optimal selectivity of olefins over paraffins. The ab initio modeling is then applied to identify realistic nanomaterials that will produce such conditions. The second case, [alpha]-Fe₂O₃, commonly known as hematite, is potential solar cell material. I demonstrate the use of a screened search through chemical compound space in order to identify doped hematite-based materials with an ideal band gap for maximum solar absorption. The electronic structure of hematite is poorly treated by standard density functional theory and requires the application of Hartree-Fock exchange in order to reproduce the experimental band gap. Using this approach, several potential solar cell materials are identified based on the behavior of the dopants within the overall hematite structure. The final aspect of this work is a new method for identifying low-energy chemical processes in condensed phase materials. The gap between timescales that are attainable with standard molecular dynamics and the processes that evolve on a human timescale presents a challenge for modeling the behavior of materials. This problem is particularly severe in the case of condensed phase systems where the reaction mechanisms may be highly complicated or completely unknown. I demonstrate the use of support vector machines, a machine-learning technique, to create transition state theory dividing surfaces without a priori information about the reaction coordinate. This method can be applied to modeling the stability of novel materials. / text

The theoretical description of bistable materials requires dealing with the interplay of various phenomena, like temperature, environmental effects and electron correlation. We developed a procedure to combine the benefits of the molecular dynamics techniques with the accuracy of the ab initio wave function based methods including various models for the surroundings. The combination of these computational methods involved the making of specific software tools. The proposed procedure has been applied successfully, obtaining good agreements with experimental data, on organic molecules in solvent (cytosine tautomers in water), crystalline materials (NiO, LaMnO3 and TTTA) and inorganic spin-crossover compounds (FeII(bpy)3). We achieved a significant improvement in the description of their absorption spectra: including ligand-to-metal and metal-to-metal charge transfer processes, formally dipole forbidden transitions and the broadening of the spectral bands. Moreover, we observe dramatic changes on the electronic structure by incorporating the environmental effects on the theoretical model. / La descripció teòrica de materials biestables requereix el tractament de diversos fenòmens interactuants, com la temperatura, els efectes del medi i la correlació electrònica. S'ha desenvolupat un procediment que combina els beneficis de la dinàmica molecular amb la precisió dels mètodes ab initio basats en la funció d'ona incloent diferents models de l'entorn. La combinació d'aquests mètodes computacionals ha involucrat la creació de programari específic. El procediment proposat ha estat aplicat amb èxit, obtenint bona concordança amb els experiments, a molècules orgàniques en solvent (citosina en aigua), materials cristal•lins (NiO, LaMnO3 i TTTA) i compostos spin-crossover inorgànics (FeII(bpy)3). S'ha assolit una millora significativa en la descripció del seus espectres d'absorció: incloent la transferència de càrrega lligand-metall i metall-metall, les transicions formalment prohibides per dipol i l'eixamplament de les bandes espectrals. A més, s'observen canvis importants en l'estructura electrònica al incorporar els efectes de l'entorn en el model teòric.