In this study we synthesized poly(tyrosine) (PTyr) through living ring-opening polymerization of £\-amino acid-N-carboxyanhydride and then blended with poly(4-vinyl pyridine) (P4VP) homopolymer in N, N-dimethylformamide (DMF) and methanol solutions to control the miscibility behavior and the secondary structures of poly(tyrosine). Infrared spectrum analysis suggests that the mixture of PTyr/P4VP possesses strong hydrogen-bonding interaction between the hydroxyl group of PTyr and the pyridine group of P4VP. DSC analyses indicate that these PTyr/P4VP complexes from methanol solution always have higher glass transition temperatures than the corresponding PTyr/P4VP miscible blends obtained from DMF solution. We proposed that the polymer chain behavior of PTyr/P4VP blend from DMF solution is the separated random coil and thus the PTyr chain possesses the random coil secondary structure after solvent evaporation. However, by increasing the hydrogen bonding for PTyr/P4VP complex from methanol solution, inter-polymer complex aggregate is proposed and the corresponding chain behavior enhances the intermolecular hydrogen bonding interaction of PTyr with P4VP that results in the £]-sheet conformation based on Fourier transforms infrared (FTIR), solid state nuclear magnetic resonance (NMR) spectroscopy, and wide-angle X-ray diffraction analyses.

Differential scanning calorimetry (DSC), 13C solid state nuclear magnetic resonance (SSNMR), one- and two-dimensional fourier transform infrared spectroscopes (FT-IR), Gel Permeation Chromatography (GPC) have been used to investigate the miscibility behavior and specific interactions of Poly(3-hydroxybutyrate), (PHB) blending with poly(styrene-co-vinyl phenol), (PS-co-PVPh) through hydrogen bonding complex upon varying the vinyl phenol contents in copolymer. We describe FT-IR spectra reveal that hydrogen bonding between carbonyl and phenol. A miscibility window exists when the vinyl phenol fraction in the copolymer is greater than 20 mol% in the PHB/PS-co-PVPh blend system, as predicted using the Painter¡VColeman association model. The vinyl-terminated benzoxazine (VB-a), which can be polymerized through ring opening polymerization, was synthesized through the Mannich condensation of bisphenol A, formaldehyde, and allylamine. This VB-a monomer was then blending with epoxy resin, followed by thermal curing concurrently, to form epoxy/VB-a copolymers network. To understand the curing kinetics of this epoxy/VB-a copolymer, dynamic differential scanning calorimetry measurements were performed by Kissinger and Flynn-Wall-Osawa methods. The FTIR analyses revealed the presence of thermal curing reactions and hydrogen bonding interaction of epoxy/VB-a copolymers. Meanwhile, the significant enhancement of the ring opening and allyl polymerizations of the epoxy was observed. For these IPNs, DMA and TGA results indicate that the thermal properties increase with the increase of VB-a contents in epoxy/VB-a copolymers.

The effect of hydrogen bonding on the conformation of organic moleculesunifies two projects in this thesis. In one project, the stability of the intramolecularhydrogen bond in derivatives of 2-guanidinobenzimidazole was studied bydynamic 1H NMR spectrometry. The impact that this intramolecular hydrogenbond had on the bond order of the neutral guanidino group and on the dynamicconformation of these aromatic structures was related to the concept of hydrogenbond-assisted resonance. In another project, an oligomer possessing repetitiveconformation and capable of much inter- and intramolecular hydrogen bondingwas designed and synthesized. The sensitivity of this oligomer to changes inanion concentration, as well as its own propensity to self-aggregate weremeasured.Hydrogen bonds found in many biological oligomers are connected thougha system of conjugated bonds. Guanidinobenzimidazole is a conjugated systemof carbon and nitrogen, connected by an intramolecular hydrogen bond. Severalderivatives of guanidinobenzimidazole were synthesized, and the effect ofseveral simple alkyl for hydrogen substitutions were studied.Guanidinobenzimidazole was used as a model to study what effect theconjugation and the intramolecular hydrogen bond have on each other.The formation of redundant low energy hydrogen bonds is universal inbiological oligomers. In DNA and RNA multiple hydrogen bonds are formed witha typical energy contribution of only 1-2 kcal/mol. Individually, these interactionsdo not give the biological oligomers their conformational stability, but togetherthey are very stable. The urea and amide based oligomers designed in the workand discussed in the thesis should form multiple hydrogen bonds withthemselves and/or with anionic guests. Chiral oligoureas were designed topossess this characteristic of cooperative conformation that so many biologicaloligomers and polymers share.

Design of selective non-covalent binding systems for chemical and biological recognition requires an intimate understanding of the factors that control the strength of each interaction. Weak interactions such as anion-Π, Π-Π, and CH-Π are understood to be important contributors to the overall binding of ligands, however, these interactions are almost purely electrostatic. Aryl CH hydrogen bond donors are a recent addition to the field and provide new possibilities by introducing a partial covalent character, which imparts greater directionality and acceptor preference. CH hydrogen bonds, and other similar weakly polarized donors, are an exciting development in supramolecular chemistry because of their ubiquity, stability and structural diversity. The use of experimental and computational techniques in this dissertation has provided us with a new understanding of the energetic factors that control CH hydrogen bond strength and selectivity for anion binding. 2,6-bis(2-anilinoethynyl) receptors with an aryl CH donor as the central arene act as anion receptors with one CH hydrogen bond and four supporting NH hydrogen bonds around a semi-preorganized pocket. The scaffold provides an efficient route to substitution para to the donor, which allows for tuning of optoelectronic properties and the measurement of linear free energy relationships (LFERs) on anion binding. Association constants with anions, Cl^-, Br^-, I^-, NO3^-, were measured by ¹H NMR and UV-vis spectroscopy in water saturated chloroform. The solution data was combined with calculated and empirical measurements to provide LFERs and identify an anion dependent substituent character. The importance of substituent resonance or inductive character has been further probed by measuring the isotope effect of selective monodeuteration. Solution measurement of a normal equilibrium isotope effect points to the role of covalency in this non-traditional hydrogen bond. The application of this new understanding to developing fluorescent probes for biological and environmental anions is demonstrated with a small receptor array. This dissertation includes both previously published and unpublished co-authored material.

We approximate the vibrational energies of the symmetric and asymmetric stretches of the hydrogen bonds of the molecules H_3O_2^- and H_5O_2^+ by applying an improvement to the standard time-independent Born-Oppenheimer approximation. These two molecules are symmetric around a central hydrogen which participates in hydrogen bonding. Unlike the standard Born-Oppenheimer approximation, this approximation appropriately scales the hydrogen nuclei differently than the heavier oxygen nuclei. This results in significantly more accurate approximations for the stretching vibrational energies, which we compare to experimental measurements. / Master of Science

<p dir="ltr">In computer-aided drug discovery, methods that are approximate, but computationally inexpensive play an essential role during the initial phase of the discovery process. Although often inaccurate, they enable the screening of vast drug libraries to identify potential inhibitors with favorable activities, before large amounts of computational resources could be dedicated to studying these individual molecules. This thesis presents<b> </b>such an approach, based on the concept of hydrogen bond wrapping, to study protein-ligand interactions in the context of drug discovery. The ‘wrapping’ refers to the tendency of hydrophobic groups to surround a hydrogen bond in water, leading to its desolvation, thereby stabilizing it.</p><p dir="ltr">Herein, a molecular descriptor was employed, which quantifies the extent of hydrophobic wrapping around a protein’s backbone hydrogen bonds (BHBs) and could help speed up the discovery process by providing cues for the design or optimization of inhibitors. Additionally, these insights could help tailor not just the binding affinity of inhibitors, but also their specificity toward an intended target protein. The human transmembrane protease serine 2 (TMPRSS2) was used as an illustrative target protein due to the pressing need for COVID-19 therapeutics, and since the current understanding of the binding mechanisms of known TMPRSS2 inhibitors is limited.</p><p dir="ltr">Molecular docking with a Generalized Born - surface area (GBSA) scoring function was first performed to virtually screen for TMPRSS2 inhibitors. The molecular descriptor was then used to analyze the change in wrapping groups of TMPRSS2 BHBs due to docked ligands, with the aim of identifying BHBs with a high propensity for desolvation. The BHBs involving residues Cys437, Gln438, Asp440, and Ser441 of TMPRSS2 were seen to have some of the largest average increases in wrapping. These general results were also compared to results from docking of the known TMPRSS2 inhibitors, camostat, and nafamostat.</p><p dir="ltr">The data generated from docking were then used to examine potential applications of the wrapping molecular descriptor using machine learning techniques: (i) for prediction of the solvent-accessible surface area term ΔG_sa of the GBSA score using regression and (ii) for classifying the solvent interactions of a TMPRSS2-inhibitor complex as favorable or unfavorable. The descriptor was seen to be only weakly related to ΔG_sa; the best-performing regression model had a Pearson correlation coefficient of 0.76 between the predictions and the actual values. The ability of the descriptor to classify solvent interactions was more satisfactory, with a highest value for area under the receiver operating characteristic curve of 0.75.</p><p dir="ltr">The descriptor was then used to analyze the effect of inhibitor binding on the dynamics of TMPRSS2 BHBs. For this, molecular dynamics simulation was carried out for the uncomplexed TMPRSS2, as well as its complex with known inhibitors and hit molecules from docking. The binding of these ligands was seen to improve the stability of TMPRSS2; certain BHBs which were unstable or not formed in the uncomplexed case, showed increased stability. These prominently included a couple of BHBs identified from docking as having gained a large increase in wrapping. The improved stability coincided with an increase in wrapping groups in several cases. The descriptor also successfully rationalized the desolvation of a few BHBs due to inhibitor binding.</p><p dir="ltr">This work demonstrates the potential application of the concept of hydrogen bond wrapping in understanding the mechanism of inhibitor binding and the resultant desolvation effects on a protein’s BHBs, without computationally expensive calculations. While the analysis methods require further improvement, the wrapping descriptor shows promising results and could be developed into a simple, yet powerful tool for drug discovery.</p>

Doctor of Philosophy / Department of Chemistry / Christer B. Aakeröy / Co-crystallization allows the manipulation of physical properties of a given compound without affecting its chemical behavior. The ability to predict hydrogen bonding interactions, provides means to the rational design of supramolecular architectures. It also makes it possible to select with a degree of accuracy, a few co-formers that have a high probability of forming co-crystals with a compound of interest, instead of blindly screening against a large number of candidates. To study the effects of changing electronic environment on the ability to form co-crystals, five symmetric dioximes of different hydrogen bond donating ability were synthesized with different functional groups on the carbon α to the oxime moiety. It was shown that the supramolecular yield increase with the positive MEP value on the donor site. In order to further explore this relationship between calculated MEP values and supramolecular selectivity three asymmetric ditopic donors containing phenol carboxylic acid and aldoxime groups were screened against a series of asymmetric ditopic acceptors. Nine crystal structures show that the supramolecular outcome can be predicted according to Etter’s rules by ranking donors and acceptors according to calculated MEP values. To explore the possibility of using the same approach with other hydrogen bond donors, three asymmetric ditopic donor ligands containing cyanooxime groups were synthesized and screened against a series of asymmetric ditopic acceptors. Nine out of ten times the supramolecular outcome could be predicted by MEP calculations 1-deazapurine exists in two tautomeric forms (1H and 3H) in aqueous solution, which have very different hydrogen bonding environments. The 3H tautomer forms a self-complementary dimer involving a donor and an acceptor site leaving a second acceptor site vacant. In order to stabilize this tautomer the molecule was screened against a of series hydrogen and halogen bond donors. Four out of five structures obtained showed 3H tautomer. The 1H tautomer is the geometric complement of urea. Therefore the molecule was screened against a series of N,N-diphenylureas and all five structures showed the 1H tautomer.

No description available.

Having a net dipole moment, water molecules tend to align with an external electric field. The re-orientation of water molecules to align with the field direction can result in structural and dynamic changes in liquid water. Studying these changes can help us to understand the role of an E-field in many biological systems, chemical reactions, and many technological advancements. In short, the application of static electric fields causes molecules to stay aligned with the field, so, fewer hydrogen bonds break, and molecules have slower dynamics. This type of field can be used when the mobility of water molecules needs to be reduced, like in electroporation. Alternating electric fields, on the other hand, cause continuous re-orientation of dipole moments, which results in more H bond breaking, water is less structured, and molecules have faster motion. Water under static and alternating electric fields have several applications in science and technology. Although many of the interesting usages of the application of electric fields to water happen at surfaces, the response of hydrogen bonding of water molecules to an E-field is still not fully understood even in bulk. For instance, the rate of hydrogen bond breaking, the re-orientation of water molecules, and the random walk of water molecules under the restrictions of the static electric field have not been thoroughly assessed. The static electric field limits the re-orientation of water molecules, but the translation reduces at the same time, this is clear evidence of roto-translational coupling, and the static electric field is a great groundwork for studying this coupling which is generated by the hydrogen bonds. For studying the effects of an E-field on H-bonding dynamics in depth, we need a model of hydrogen bonding. There are a few models for dynamics of H-bonding and reorientation of water molecules, including Luzar and Chandler model, published in 1996, and the Laage and Hynes jump model, published in 2006, which are described in the introduction chapter. The two models are related but have different perspectives, so it would be very interesting to look for a more general framework of hydrogen bonding by combining these two models, with the help of the influence of external electric fields. We also explain the relation of the random walk diffusion of water molecules and the hydrogen bonding. Since the external electric field can change the dipole moment of water molecules, for a more realistic picture, we need do the simulations with sophisticated polarizable water models to obtain a better estimate of the behavior of experimental water in an electric field. In this thesis, we introduce our generalized hydrogen bond framework; then we assess this framework, as well as other static and dynamic properties of water under static and alternating electric fields.

A series of immiscible crystalline-crystalline diblock copolymers, poly(ethylene oxide)-b-(£`-caprolactone) (PEO-b-PCL), were synthesized through ring-opening polymerization and then blended with phenolic resin. FT-IR analyses provide that the ether group of PEO is a stronger hydrogen bond acceptor than the carbonyl group of PCL with the hydroxyl group of phenolic. Phenolic after curing with hexamethylenetetramine (HMTA) results in the excluded and confined PCL phase based on differential scanning calorimeter (DSC) analyses. This effect leads to the formation of a variety of composition-dependent nanostructures, including disorder, gyroid and short cylinder. The self-organized mesoporous phenolic resin was only found at 40~60 wt% phenolic content by intriguing balance of the contents of phenolic, PEO, and PCL. In addition, the mesoporous structure was destroyed with the increasing the ratio of PCL to PEO in block copolymers by small angle X-ray scattering (SAXS) and transmission electron microscopy (TEM) analyses. In addition, the large and long-range order of bicontinuous gyroid-type mesoporous carbon was obtained from mesoporous gyroid phenolic resin calcined at 800 ¢XC under nitrogen.