Thesis (Ph. D.)--Ohio State University, 2009. / Title from first page of PDF file. Includes vita. Includes bibliographical references (p. 229-245).

Thesis (M.S.)--Florida State University, 2005. / Advisor: Dr. Igor Alabugin, Florida State University, College of Arts and Sciences, Dept. of Chemistry and Biochemistry. Title and description from dissertation home page (viewed Sept. 19, 2005). Document formatted into pages; contains xv, 123 pages. Includes bibliographical references.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1967. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Ph.D.) -- McMaster University, 2001. / Includes bibliographical references (leaves 170-174).

Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2006. / Includes bibliographical references. Also available in electronic version.

Thesis (Ph.D.)--Duquesne University, 2009. / Title from document title page. Abstract included in electronic submission form. Includes bibliographical references (p. 212-246) and index.

Le concept de liaison chimique compte parmi les plus importants de la chimie car il permet de décrire aussi bien les propriétés chimiques d'un système que de comprendre et prédire les réactions chimiques. L'objectif principal de cette thèse est l'étude de nouveaux types d'interactions chimiques impliquant l'atome de béryllium. L'atome Be présente d'importantes propriétés chimiques en raison de la basse énergie des orbitales pBe. Compte tenu de leur toxicité, les composés de béryllium ont été relativement peu étudié sur le plan expérimental. Nous rapportons une analyse théorique de trois nouveaux types de liaison impliquant le béryllium en utilisant des méthodes ab-initio de haut niveau, la théorie de la fonctionnelle de la densité (DFT), ainsi que l'application du Tenseur de Spread de la Position Totale (TPS, pour l'acronyme en anglais Total Position Spread tensor) aux systèmes moléculaires. Tout d'abord, la liaison béryllium non-covalente (BerB, pour l'acronyme en anglais Beryllium Bond). Ce type de liaison se forme grâce à une interaction entre un dérivé du Be agissant comme un Acide de Lewis (LA) fort et une Base de Lewis (LB). L'interaction entre un LA du béryllium et des dérivés du fluor génère un shole dans l'atome de fluor, qui n'aurait pu être créé autrement, ce qui rend possible la conception de nouveaux matériaux où l'atome de fluor se lie à travers des liaisons halogènes. Cette même interaction diminue leur énergie de liaison F-R, en changeant la dissociation homolytique du F-R en un processus exothermique. Par conséquent, les BerB peuvent être utilisés pour produire spontanément des espèces radicales. La Liaison béryllium intramoléculaire (IBerB) ont été étudiés dans les systèmes de type malonaldéhyde et tropolone. Cette interaction intramoléculaire devient plus forte dans les systèmes insaturés, parce que la LA et la LB sont plus acides et basiques, respectivement. Deuxièmement, la liaison Be-Be intramoléculaire dans les complexes de naphtalène doublement substitués. Les espèces anioniques dérivées du 1,8-diBeY1-naphtalène montrent une très forte liaison Be-Be mono-électronique. Cette liaison est huit fois plus forte et 0.5Å plus courte que le dimère isolé. Ces systèmes présentent haute affinité électronique, ce qui leur donne une propriété exceptionnelle : la capacité d'agir comme des on les appelle éponges anioniques. Il a été découvert que les interactions entre les anions et le naphtalène doublement substitué présente des affinités anioniques parmi les plus élevées, comparé à ce qui a été publié dans la littérature sur le composés neutres. Ce qui pourrait conduire à une grande variété d'applications dans le domaine des récepteurs et des capteurs d'anions. Troisièmement, l'interaction entre la molécule Be2 et a LB, qui a montré pour augmente la force de la liaison Be-Be par rapport à la molécule isolée. L'interaction non-covalentes dans les complexes du type L : Be-Be : L diminue la distance et augmente l'énergie d'interaction de la liaison Be-Be. L'effet sur la fraction Be2 dépend de la nature des bases de Lewis. / The chemical bond is among the oldest and most important concepts in chemistry because it allows to describe chemical properties of a system, as well as to understand and predict chemical reactions. The main goal of this PhD thesis is to study new types of chemical interactions involving the beryllium atom. Be atom has a rich chemistry due to its low-lying pBe orbitals, but its high toxicity has limited the number of experimental studies, enhancing the importance of theory in the description of Be compounds. This thesis reports the theoretical analysis of three new types of Be bonds using high-level ab-initio and Density Functional Theory, and the applications of the Total Position Spread Tensor (TPS) to molecular systems. First, the non-covalent Beryllium Bonds (BerB). This type of bond is formed by an interaction between a Be moiety acting as a strong Lewis Acid (LA) and a Lewis Base (LB). The interaction between beryllium LA and fluorine derivatives (FR) generates a shole in the fluorine atom, otherwise not possible, opening the possibility to design new materials where fluorine binds through halogen bonds. This same interaction decreases the F-R bond energy, turning the F-R homolytic dissociation in an exothermic process, and suggesting BerBs can be used to produce spontaneously radical species. Moreover, in this thesis, Intramolecular Beryllium Bonds (IBerB) were studied in malonaldehyde- and tropolone-like systems. This interaction is stronger in unsaturated systems than in their saturated analogues due to the increase of the acidity and basicity of the LA and LB, respectively. Second, the intramolecular Be-Be bond in disubstituted naphthalene complexes. The anion species of 1,8-diBeY1-naphthalene derivatives show a very strong one-electron Be-Be bond. This bond is eight times stronger and 0.5 Å shorter than the one in the isolated dimer. These systems present high electron affinities, which give to them an exceptional property: the ability to behave as what we have named anion sponges. It was found that the interaction between anions and Be disubstituted naphthalene is among the highest anion affinities reported in the literature for neutral compounds. This property could lead to a wide range of applications as anions receptors and sensors. Third, the interaction between the Be2 molecule and Lewis bases, which has shown to en-hance the strength of the Be-Be bond compared with the isolated molecule. The non-covalent interaction in complexes of the type L : Be-Be : L decreases the distance and increases the strength of the Be-Be bond. The effect over the Be2 moiety depends on the nature of the Lewis bases. The most dramatic effect occurs when L are radical species. The Be-Be bond in this type of complexes is among the strongest reported in the literature due to an increase of the Be2 oxidation state from Be0 to Be2+. The same effect is found in ligands with pL orbitals, which conjugate with the pBe orbitals and increase the oxidation state of the Be2 moiety to +1. Therefore, the Be-Be interaction becomes stronger than the free Be2 molecule, although still weaker than that of complexes with radical species. At last, the complexes where the Be2 moiety remains neutral and interacts with the lone pairs of the LB show, to the best of our knowledge, the strongest Be-Be bond reported in the literature for the neutral Be dimer. Finally, the TPS is proposed as a new method for the description of chemical bonds. The TPS is quantity that describes the electron and spin fluctuation when a system is perturbed. In this PhD thesis the TPS is applied to diatomic molecules and to Be-carbonyl derivatives. The tensor shows a different behavior depending on the type of interaction, thus allowing the distinction between a covalent, ionic, charge-shift, and other types of bonds, and at the same time the tensor identifies the electron correlation nature of the system.

The immune system produces antibodies to recognize and provide protection against infection. The immunoglobulin G (IgG) antibody isotype is present at high serum concentrations and has a longer half-life than other isotypes due to the interaction between its fragment crystallizable (Fc) region with the neonatal Fc receptor (FcRn). This Fc-FcRn interaction, which takes place in many cell types throughout the cardiovascular system, mediates pH-dependent formation of the IgG-FcRn complex and leads to the rescue of IgG from eventual degradation via transport from the low-pH early endosome back to the cell surface for release into serum at pH 7.4. Because this process is the primary determinant of IgG antibody half-life, and because the Fc region is common to all antibodies of the same subtype, the Fc-FcRn system has been a target of numerous antibody design and engineering studies. Indeed, several engineered Fcs have been reported with extended serum half-lives. These novel Fc variants, however, have generally been the result of extensive experimental screening and combinations of individual Fc mutations with known biophysical properties; there are few reports of predominantly structure-based rational Fc design. Notably, simply increasing Fc binding affinity for FcRn at low pH does not appear to be sufficient to achieve the largest increases in half-life (and in some cases, very high affinity results in reduced serum half-life). Most of these engineered Fcs have increased affinity not only at low pH (~6.0), but also at pH 7.4. The longest-lived Fc variant known to date, however, with mutations L309D/Q311H/N434S (“DHS”), has only a modest 5-fold increase in binding affinity compared to wt Fc at low pH, but also exhibits negligible binding to the receptor at pH 7.4 (Lee et al., 2019). This is consistent with previous reports that identify efficient release at physiologic serum pH to be critical to FcRn-mediated half-life extension. Thus, while engineering for affinity at low pH, it is also important to optimize the pH dependence of binding for optimal release at serum pH. The rational design process requires a detailed understanding of the structural and functional details of the interaction, which for a pH-dependent complex like Fc-FcRn must also include an accurate model of the pH-sensing mechanism. Unfortunately, the only publicly available crystal structure of a human Fc-FcRn complex is of the M252Y/S254T/T256E (“YTE”) variant, and was determined only to a relatively low 3.8 Å resolution, leaving the atomic positions of many sidechains, and even regions of the protein backbone, subject to substantial uncertainty. Furthermore, the widely accepted conventional mechanism of pH sensing, involving protonation of key histidine residues on Fc at low pH due to the assumed histidine pKa of 6.5 being within the range of interest (pH 6.0-7.4), is thermodynamically impossible. In this thesis I present an extensive analysis of the Fc-FcRn system, including the generation of all-atom models of human wild-type (wt) and variant complexes and the rat wt complex, and assignment of dominant protonation states at pH 6.0, at which most binding experiments are performed. I validate these models using retrospective molecular dynamics (MD)-based free-energy perturbation (FEP) calculations to compare to a large dataset of wt and mutant binding affinities. During this validation process I identify a residue on FcRn, glutamic acid 133, which adopts a highly unusual configuration in the complex and, due to quantum mechanical electronic polarization effects, is not described well by the fixed-charge molecular mechanics force field used by the FEP calculations, resulting in systematic errors for mutations that affect its hydrogen bonding network. I also identify a new variant, with a V308P mutation in a YTE background (“YTEP”), which induces a previously unreported conformational change that accounts for its high binding affinity compared to YTE and wt. To address the problem of the pH-sensing mechanism, I describe a general method for calculating the pH-sensing free energy of binding for any complex, based on a study of the pH dependence of protein unfolding free energies (Yang and Honig, 1993). The key observation underlying this method is that pH-dependent complex formation must be accompanied by a change in the pKa of one or more titratable groups between the unbound and bound states. Furthermore, the change in binding energy between two pHs can be directly calculated based on those pKas alone. As there are no experimental pKa measurements available for the Fc-FcRn interface residues, I perform these pH-sensing free energy calculations using FEP-based calculated pKas to quantitatively assess which residues at the interface are involved in sensing pH over the physiologically relevant pH range, and present a residue-level model for pH sensing in the Fc-FcRn system. Finally, I present some preliminary work toward the rational design of modified Fc regions with both increased affinity at low pH, and increased pH dependence of binding, using FEP calculations to guide experiment. This type of approach, of computational screening of a large number of different variants, followed by more limited experimental testing of promising leads, has the potential to streamline Fc design efforts and provide further insight into the structural basis of function for the Fc-FcRn system.

Biaryl moieties are important structural motifs in many industries, including pharmaceutical, agrochemical, energy and technology. The development of novel and efficient methods to synthesize these carbon-carbon bonds is at the forefront of synthetic methodology. Since Ullmann’s first report of stoichiometric Cu-mediated homo-coupling of aryl halides, there has been a dramatic evolution in transition metal catalyzed biaryl cross-coupling reactions. Our work focuses on the discovery and development of an unprecedented reagent combination for metal-free cross-coupling. It is hypothesized that direct carbon-carbon bond formation occurs via a triaryl-λ3-iodane and that electrophile/nucleophile pairing is critical for success in the reaction. Proof-of-concept for this approach focused on the reaction between bromo 4-trifluoromethylphenyl (trimethoxybenzene)-λ3-iodane and potassium 3-fluorophenyltriolborate. The spectator ligand and counter ions are important parameters for both reactivity and selectivity of the aryl group transfer in this reaction. Moderate to good yields of biaryl products are obtained by this method. Experimental evidence supports the assertion of a metal-free cross-coupling reaction.

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