Protein molecules, sometimes referred to as the molecules of life, are the drivers of virtually every biological function. In this dissertation, we describe a series of computational studies to dissect the mystery of complex protein molecules. We consider a large collection of protein systems, ranging from globular proteins to Intrinsically Disordered Proteins (IDPs) with a focus on predicting thermodynamic observables that can be quantitatively compared with experimental data. In the first part of this dissertation, we study the effects of the phenomenon of macromolecular crowding and how it affects the properties of two different groups of proteins. First, we investigate the effects of crowding on globular proteins by calculating the free energy of all-atom proteins in crowded environments. Second, we study how crowding affect the conformational ensembles of disordered proteins with a focus on comparing computations with experiments. In the second part of this dissertation, we apply Monte Carlo simulation techniques to study protein droplet formation and Liquid Liquid Phase Separation in protein systems. / A Dissertation submitted to the Department of Physics in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Fall Semester 2018. / November 06, 2018. / Intrinsically Disordered Proteins, Monte Carlo simulations, Protein Droplets, Proteins / Includes bibliographical references. / Jorge Piekarewicz, Professor Directing Dissertation; Scott Stagg, University Representative; Huan-Xiang Zhou, Committee Member; Peng Xiong, Committee Member; David Van Winkle, Committee Member.

Monolayer organic thin films and heterostructures are of great interest for their optical and electronic properties and as systems which allow the interplay between the structural and functional properties of organic molecules to be investigated. In the first experimental section of this thesis, sub-monolayer coverages of perylene tetracarboxylic diimide (PTCDI) were grown on hBN substrates and found to form needle-like monolayer islands at room temperature, while higher growth temperatures gave larger monolayer islands. The molecular packing of monolayer PTCDI was confirmed, using AFM, to correspond to the canted phase. The 0-0 fluorescence peak of this structure was found to occur at 2.208 ± 0.002 eV. The fluorescence of multi-layer PTCDI samples was mapped, with additional peaks measured at 2.135 ± 0.002 eV (580.7 ± 0.5 nm) and 2.118 ± 0.002 eV (585.4 ± 0.5 nm). Relating the morphology and fluorescence of such films using AFM and fluorescence microscopy is a promising way to investigate structural effects on the optical properties of multi-layer organic systems. Using solution deposition techniques, the PTCDI-melamine supramolecular network and the canted phase of PTCDI were deposited on hBN. The molecular packing of both structures was confirmed using AFM and the 0-0 fluorescence peaks were measured to be 2.245 ± 0.002 eV and 2.214 ± 0.002 eV for the PTCDI-melamine network and PTCDI respectively. The fluorescence of sublimed PTCDI, solution deposited PTCDI, PTCDI-melamine and measurements of Me-PTCDI doped helium nano droplets (HND) were compared. A 0.031 ± 0.002 eV red shift was measured from PTCDI-melamine to PTCDI while a 0.346 ± 0.002 eV red shift was measured from doped HND to PTCDI on hBN. A second perylene derivative, perylene tetracarboxylic dianhidride (PTCDA), was also deposited on hBN. Comparing the fluorescence of PTCDA monolayers on various dielectric substrates suggested a large shift due to the coupling of transition dipole moments and image dipoles beneath the dielectric surface. The shift between PTCDI and PTCDI-melamine was attributed to the coupling of transition dipole moments, for which the exciton bandstructure of both phases has been calculated with and without screening. The growth of sublimed C60 was also investigated, with monolayer islands observed for growth at room temperature and faceted bi-layer islands observed at 212 °C. The growth of PTCDI/C60 ¬heterostructures was also investigated, with C60 found to form monolayer islands on monolayer PTCDI at room temperature. At higher growth temperatures, C60 was found to form multilayers, with a reduced island density at PTCDI island edges, suggesting upward and downward hopping from the PTCDI surface to the second C60 layer and hBN respectively. C60 was found to quench the fluorescence of PTCDI and led to a 0.032 ± 0.02 eV blue shift. Finally, the growth of cyanuric acid-melamine (CA.M) on CVD graphene and CA.M/PTCDI heterostructures on hBN was investigated. Cyanuric acid-melamine was found to form monolayers with a honeycomb packing structure on CVD graphene. On monolayers of CA.M, PTCDI was found to form needle-like monolayer islands, the row direction of PTCDI is thought to have an on-axis registry with the substrate. Finally, the fluorescence of CA.M/PTCDI heterostructures on hBN was measured, with a 0.045 ± 0.002 eV blue shift from PTCDI on hBN.

Typescript (photocopy). / Digitized by Kansas Correctional Industries

Taking advantage of cutting-edge technologies in computational and experimental chemistry, my Ph. D. research aimed to bridge both of these chemical subdivisions. Therefore, while part I of this dissertation focuses on new structure-based computational methodologies to predict selectivities of organic and enzymatic reactions, part II is concerned with the design, the synthesis and the electrical properties of novel, single molecular wires. These single molecule technologies described in part II are likely to contribute to more powerful computer chips in the future, which will in turn lead to faster and more accurate computational predictions for chemical problems. Part I: Computers for Chemistry: Progress towards the design of accurate computational tools to predict the selectivity of chemical reactions. The first fully quantum mechanical study to predict enantioselectivities for a large dataset of organic reactions has been reported. Enantioselectivities were calculated for a diverse set of 46 dioxirane catalyzed epoxidation reactions. Comparison to experiments showed that our methodology is able to accurately predict the free energy differences between transition states leading to enantiomeric products. To further improve the predictive performance, we have also developed a new correction scheme, which increases the accuracy of density functional theory (DFT) for non-covalent interactions. Our new correction scheme accurately estimates interaction energies of non-covalent complexes not only with large, but also with small basis sets at lower computational cost. The improved enantioselectivity prediction protocol containing our latest non-covalent corrections has now been fully automated in a user-friendly fashion. We are currently testing its accuracy for other asymmetric reactions, such as CBS reductions and are also trying to use our methodology to design new asymmetric organocatalysts. In collaboration with Dr. Jianing Li, a structure based computational methodology to predict sites of metabolism of organic substrates with P450 enzymes has also been developed, which is highly relevant for structure-based drug discovery. Part II: Chemistry for Computers: From novel antiaromatic and pi-pi-stacked molecular wires to highly conducting link groups with direct Au-C bonds. Part II of this dissertation describes studies of antiaromatic and pi-pi-stacked molecular wires as well as new direct ways to connect them to gold electrodes. At the beginning, the first successful single molecule conductance measurements ever on partially antiaromatic molecular wires are described. These wires, based on a biphenylene backbone, were synthesized via a highly regioselective cyclization enabled by the antiaromaticity. Then, two new ways to connect single molecules to gold electrodes with direct Au-C links are presented. The first methodology is based on strained arene rings in [2.2]-paracyclophanes, which were found to directly contact gold electrodes with their pi-systems. The second methodology employs tin based precursors, which get replaced in situ by gold electrodes to also form direct Au-C bonds with very low resistance. The direct Au-C bonds observed with strained paracyclophanes enabled us to study, for the first time, single molecule conductance through multiple layers of stacked benzene rings. Further single molecule conductance studies with less strained stacked benzene rings are currently under way and will provide additional valuable evidence about electron transport in stacked pi-systems.

Polymeric and metal oxide micro- and nanoparticles are being increasingly introduced into biomedical applications such as tissue engineering as well as in consumer products, which has boosted extensive research towards developing predictive paradigms of their (bio-)activity. The core hypotheses which are tested in the four interrelated studies of this work is that the (bio-)activity of the particles is defined not only by their intrinsic properties such as the composition/structure, functional groups, surface charge, and size/morphology, but also on the concentration of particles which in turn is determined by specific applications. In addition, the (bio)activity of the particles can be controlled by the application-specific biomolecules or surfactants. These hypotheses are tested on polymeric and metal oxide particles from the perspective of their application in tissue engineering of articular cartilage and consumer products (antioxidant additives and dyes), respectively. The modeling of the transport properties of biomaterials, as well as of the adsorption properties of metal oxide nanoparticles can help to determine or interpret the observed relationships.

This thesis describes the development and application of microscopically-defined theories of excitons in a wide range of semiconducting materials. In Part I, I consider the topic of singlet exciton fission, an organic photophysical process which generates two spin-triplet excitons from one photoexcited spin-singlet exciton. I construct a theoretical framework that couples a realistic treatment of the static electronic structure with finite-temperature quantum relaxation techniques. This framework is applied separately, but consistently, to the problems of singlet fission in pentacene dimers, crystalline pentacene, and crystalline hexacene. Through this program, I am able to rationalize observed behaviors and make non-trivial predictions, some of which have been confirmed by experiment. In Part II, I present theoretical developments on the properties of neutral excitons and charged excitons (trions) in atomically thin transition metal dichalcogenides. This work includes an examination of material trends in exciton binding energies via an effective mass approach. I also present an experimental and theoretical collaboration, which links the unconventional disposition of excitons in the Rydberg series to the peculiar screening properties of atomically thin materials. The light-matter coupling in these materials is examined within low-energy models and is shown to give rise to bright and dark exciton states, which can be qualitatively labeled in analogy with the hydrogen series. In Part III, I explore theories of relaxation dynamics in condensed phase environments, with a focus on methodology development. This work is aimed towards biological processes, including resonant energy transfer in chromophore complexes and electron transfer in donor-bridge-acceptor systems. Specifically, I present a collaborative development of a numerically efficient but highly accurate hybrid approach to reduced dynamics, which exploits a partitioning of environmental degrees of freedom into those that evolve "fast" and "slow," as compared to the internal system dynamics. This method is tested and applied to the spin-boson model, a two-site Frenkel exciton model, and the seven-site Fenna-Matthews-Olson complex. I conclude with a collaborative analysis of a recently developed polaron-transformed quantum master equation, which is shown to accurately interpolate between the well-known Redfield and Forster theories, even in challenging donor-bridge-acceptor arrangements.

Structure and dynamics lie at the heart of the materials science. A detailed knowledge of both subjects would be foundational in understanding the materials' properties and predicting their potential applications. However, the task becomes increasingly difficult as the particle size is reduced to the nanometer scale. For nanostructured materials their laboratory x-ray scattering patterns are overlapped and broadened, making structure determination impossible. Atomic pair distribution function technique based on either synchrotron x-ray or neutron scattering data is known as the tool of choice for probing local structures. However, to solve the \structure problem" in low-dimensional materials with PDF is still challenging. For example for 2D materials of interest in this thesis the crystallographic modeling approach often yields unphysical thermal factors along stacking direction where new chemical intuitions about their actual structures and new modeling methodology/program are needed. Beyond this, lattice dynamical investigations on nanosized particles are extremely dicult. Laboratory tools such as Raman and infra-red only probe phonons at Brillouin zone center. Although in literature there are a great number of theoretical studies of their vibrational properties based on either empirical force elds or density functional theory, various approximations made in theories make the theoretical predictions less reliable. Also, there lacks the direct experiment result to validate the theory against. In this thesis, we studied the structure and dynamics of a wide variety of technologically relevant low-dimensional materials through synchrotron based x-ray PDF and high energy resolution inelastic x-ray scattering (HERIX) techniques. By collecting PDF data and employing advanced modeling program such as DiPy-CMI, we successfully determined the atomic structures of (i) emerging Ti3C2, Nb4C3 MXenes (transition metal carbides and/or nitrides) that are promising for energy storage applications, and of (ii) zirconium phenylphosphonate ion exchange materials that are proposed to separate lanthanide ions from actinide ions in nuclear waste. Both material systems have two-dimensional layered nanocrystalline structure where we observed that the stacking of layers are not in good registry, also known as "turbostratic" disorder. Consequently the signals from a single layer of atoms dominate the experimental PDF{thus building up a single slab model and simulating PDF using Debye function analysis was sucient to capture the main structural features in the measured PDF data. The information on correlation length of layers along the stacking direction, however, is contained in low-Q diraction peaks in either laboratory x-ray or synchrotron x-ray scattering patterns. On the lattice dynamics side, we first investigated the trend of atomic bonding strength in size dependent platinum nanoparticles based on temperature dependent PDF data and measured Debye temperatures. An anomalous bond softening was observed at a particle size less than 2 nm. Since Debye model gives a simple quadratic phonon density of states (PDOS) curve, which is a simplified version of real lattice dynamics, we are motivated to measure full PDOS curves on three CdSe nanoclusters by using non-resonant inelastic x-ray scattering technique. We observed an overall blue-shift of PDOS curves with decreased sizes. Our current exemplary studies will open the door to a large number of future structural and lattice dynamical studies on a much broader range of low-dimensional material systems.

Two-dimensional (2D) van der Waals materials have received widespread attention due to their novel 2D properties that are distinct from their bulk counterparts. These unique properties offer new possibilities for fundamental research and for diverse applications in electronics, optoelectronics, and valleytronics. It is therefore of great interest to design 2D materials from complex, hierarchical and/or tunable building blocks. Atomic and molecular clusters are attractive target due to their atomic precision, structural and compositional diversity and synthetic flexibility. In this thesis, we report two novel quasi-2D superatomic semiconductors: Re6Se8Cl2 and Mo6S3Br6, whose building blocks are atomic clusters rather than simple atoms. In Chapter 3, we determine the electronic bandgap (1.58 eV), optical bandgap (indirect, 1.48 eV), and exciton binding energy (100 meV) of Re6Se8Cl2 crystals by using scanning tunneling spectroscopy, photoluminescence and ultraviolet photoelectron spectroscopy, and first principles calculations. The exciton binding energy is consistent with the partially 2D nature of the exciton. In Chapter 4, the layered van der Waals material Mo6S3Br6 possesses a robust 2D character with a direct gap of 1.64 eV, as determined by scanning tunneling spectroscopy. By using polarization dependent Raman spectroscopy and DFT calculations, we determine its strong in-plane electronic anisotropy. The complex, hierarchical structures with 2D characters of these two materials thus suggest an effective strategy to expand the design space for 2D materials research with multi-functionality and novel physical properties.

Clostridium autoethanogenum is an important organism for biofuel production. Other 'omics' approaches have been used to understand the mode of operation of the organism but metabolomics gives information on the cellular activities in the cell. Metabolomics combined with other 'omics' data can provide a deeper understanding for pathway interpretation. This project sets out to develop an analytical method that is suitable for analysis of highly charged polar compounds found in C. autoethanogenum metabolic pathways. Also investigate suitable isotope labelled internal standards to improve matrix effects to the metabolites as a result of the biological matrix. A high-throughput hydrophilic interaction liquid chromatography isotope dilution mass spectrometry (HILIC-IDMS) was developed and validated using high resolution hybrid orbital trap MS for both targeted and untargeted metabolomics analysis of intracellular metabolic pathways of Clostridium autoethanogenum. Extraction of intracellular metabolites from C. autoethanogenum was achieved using a specifically developed sample preparation protocol using freeze thaw cycles (freeze in liquid nitrogen and thaw on ice repeated 3x). A total of 133 metabolites were monitored and validated. Limits of detection (LODs) ranged from 0.001 µM to 5 µM reported for compounds such as NADPH and NADH. Limits of quantification (LOQs) for all metabolites ranged from 0.001 µM to 10 µM for metabolites such as glucose-6-phosphate and glyceraldehyde-3 phosphate. Precision and accuracy were evaluated for all metabolites and found to be within the acceptable limits of ±15 % with few exceptions for some nucleotides and organic acids. Stable isotopically labelled internal standards were generated from C. pasteurianum cells that provided coverage for about 100 metabolites. This enabled absolute intracellular concentrations to be obtained in combination with the estimated cell volume of C. autoethanogenum that was obtained from microscopy and flow cytometry measurements. The developed HILIC-IDMS method was applied to various solvent production optimisation experiments conducted using C. autoethanogenum and the main findings are reported below. In chapter 4, the HILIC-IDMS method was applied to C. autoethanogenum in an experiment where the pH of the media was reduced to improve ethanol and solvent production. The metabolomics studies of this experiment gave intracellular concentrations that differentiated the acidogenic phase from the solventogenic phase. A total of 86 metabolites were quantified in this experiment. Intermediates in the tricarboxylic acid (TCA) cycle were the most affected during the acidogenic/solventogenic transition. Metabolites concentrations were used for metabolic pathways analysis to understand the pathways affected during the pH shift. The pathway analysis also confirmed the TCA cycle was the most affected pathway during the acidogenic/solventogenic transition. In chapter 5, The HILIC-IDMS method was applied to a gas shift experiment to optimise ethanol and solvent production. Gas shift is another approach that can be used to optimise solvent production in similar as the pH shift experiment. The use of gas shift to induce solventogenic phase can be difficult as C. autoethanogenum has little tolerance for high levels of CO hence the increase in gas (CO) flow rate has to be done in a gradual fashion. Equally, TCA intermediates were observed to be the most affected as observed in the pH shift experiment. In chapter 6, the method was applied to a study where pantothenate and phosphate concentrations in the growth media of C. autoethanogenum were reduced to increase ethanol production. Pantothenate is the precursor for coenzyme A (CoA) production and metabolomics study confirmed a decrease in CoA concentration when pantothenate concentration was reduced. Metabolomics also showed decrease in concentration of metabolites directly linked to CoA synthesis such as L- Aspartate. Metabolic pathway analysis also confirmed the pantothenate and CoA biosynthesis and its associated pathways were the most affected pathways during the pantothenate-limiting phase. Both targeted and untargeted metabolomics analysis were performed on these nutrient-limiting experiments and there were clear differences between the two different conditions before and after nutrient limitation. Supervised multivariate data analysis using OPLS-DA was used to compare higher pantothenate and low pantothenate concentration and there were clear separation and clustering between the two conditions. Cross validation obtained for R2Y and Q2 were 0.993 and 0.941 respectively. OPLS-DA plots for phosphate limitation also showed clustering and separation between the high phosphate concentration and reduced phosphate concentration with R2Y and Q2 0.981and 0.837 respectively. In conclusion, a novel high-throughput HILIC-IDMS method was developed and validated for analysis of different classes of polar compounds in bacteria. The method has the potential to be applied in other biological matrices for coverage of diverse range of polar compounds.

Wong Shu Yan. / On t.p. "n" is subscript. / Thesis submitted in: January 2003. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (leaves 112-115). / Abstracts in English and Chinese. / TITLE PAGE --- p.i / THESIS EXAMINATION COMMITTEE --- p.ii / ABSTRACT (ENGLISH) --- p.iii / (CHINESE) --- p.v / ACKNOWLEDGEMENTS --- p.vii / TABLE OF CONTENTS --- p.viii / LIST OF FIGURES --- p.xi / LIST OF TABLES --- p.xiii / Chapter CHAPTER ONE --- Introduction / Chapter 1.1 --- Introduction --- p.1 / Chapter 1.2 --- Solvation of clusters --- p.2 / Chapter 1.3 --- Reaction of a sodium atom with water --- p.3 / Chapter 1.4 --- Reaction of a sodium cation with methanol --- p.8 / Chapter 1.5 --- Computational Method --- p.12 / Chapter 1.5.1 --- Born-Oppenheimer (BO) Approximation --- p.12 / Chapter 1.5.2 --- Self-Consistent Fields (SCF) ´ؤ Hartree-Fock (HF) --- p.14 / Chapter 1.5.2.1 --- Moller-Plesset (MP) Perturbation Theory --- p.15 / Chapter 1.5.2.2 --- Ab Initio Molecular Orbital (MO) Calculation --- p.16 / Chapter 1.5.2.3 --- Basis Set Superposition Errors --- p.17 / Chapter 1.5.3 --- Density Functional Theory (DFT) --- p.18 / Chapter 1.5.3.1 --- Generalized-Gradient Approximation (GGA) --- p.20 / Chapter 1.5.3.2 --- Plane-wave Basis Set --- p.21 / Chapter 1.5.3.3 --- Pseudopotential Approximation --- p.21 / Chapter 1.5.3.4 --- Ab Initio Molecular Dynamics (MD) Calculation --- p.23 / Chapter CHAPTER TWO --- Reaction Mechanism of the Hydrogen Elimination Reaction of Na(H20)n clusters for n = 1 - 6 / Chapter 2.1 --- Introduction --- p.25 / Chapter 2.2 --- Computation details --- p.26 / Chapter 2.3 --- Optimized Structure of Na(H20)n and H.. .Na0H(H20)n-1 --- p.27 / Chapter 2.3.1 --- Solvation structures with n = 1-3 --- p.27 / Chapter 2.3.2 --- Solvation structures with n= 4-6 --- p.34 / Chapter 2.3.3 --- Relative energy of isomers --- p.40 / Chapter 2.3.4 --- Energy barrier of hydrogen elimination reaction --- p.42 / Chapter 2.3.5 --- Natural population analysis --- p.42 / Chapter 2.4 --- "Reaction energy for hydrogen loss in Na(H20)n, n = 1 -6" --- p.46 / Chapter 2.5 --- Ionization potential energy --- p.47 / Chapter 2.6 --- Summary --- p.50 / Chapter CHAPTER THREE --- Reaction Mechanism of the Ether Elimination Reaction of Na+(CH3OH)n cluster ions / Chapter 3.1 --- Introduction --- p.52 / Chapter 3.2 --- Computational details --- p.53 / Chapter 3.3 --- Optimized Structure for Na+(CH3OH)n (n = 1) --- p.55 / Chapter 3.4 --- Optimized Structure forNa+(CH3OH)n (n = 2-5) --- p.59 / Chapter 3.4.1 --- Na+(CH3OH)2 --- p.59 / Chapter 3.4.2 --- Na+(CH3OH)3 --- p.67 / Chapter 3.4.3 --- Na+(CH3OH)n(n = 4 and 5) --- p.75 / Chapter 3.5 --- Mechanism of ether elimination reaction --- p.79 / Chapter 3.6 --- Ab initio molecular dynamics study on Na+(CH3OH)n (n =6 and 8) --- p.85 / Chapter 3.6.1 --- Solvation dynamics for Na+(CH3OH)6 --- p.85 / Chapter 3.6.1.1 --- Dynamical structural for Na+(CH3OH)6 --- p.86 / Chapter 3.6.1.2 --- "Optimized Structures for Na+(CH3OH)n, n =6" --- p.95 / Chapter 3.6.2 --- Solvation dynamics for Na+(CH3OH)8 --- p.98 / Chapter 3.6.2.1 --- Dynamical structural for Na+(CH3OH)8 --- p.99 / Chapter 3.6.2.2 --- "Optimized Structures for Na+(CH3OH)n, n =8" --- p.106 / Chapter 3.7 --- Summary --- p.109 / REFERENCES --- p.112