<p> The study of proteasome is a rapidly evolving field with multifaceted implications in neuroscience, aging, and cancer. Recent developments structural biology of the proteasome machinery has catapulted the drug discovery and targeted protein degradation. The success of proteasome inhibitors like Bortezomib and Ixazomib has also led to new interests in developing more precise inhibitors for the various proteasome isoforms. Proteasome activation is a relatively new field, and much has to be done in the field. The 20S CP is an emerging target in chemical biology and drug discovery for its implications in maintaining protein homeostasis and immune regulation. The central theme of the thesis is to study the proteasome in cellular contexts to develop new chemical biology tools to study the proteasome and its modulation by small molecules and probes in cellular contexts to ameliorate protein accumulation-mediated neurodegeneration </p>

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The immaculate control of atoms and molecules with light is the defining trait of modern experiments in ultracold physics. The rich internal degrees of freedom afforded by molecules enrich the toolbox of precision spectroscopy for fundamental physics, and hold great promise for applications in quantum simulation and quantum information science. A vibrational molecular lattice clock with systematic fractional uncertainty at the 14th decimal place is demonstrated for the first time, matching the performance of the earliest optical atomic clocks. Van der Waals dimers of strontium are created at ultracold temperatures and levitated by an optical standing wave, whose wavelength is finely tuned to preserve the delicate molecular vibrational coherence. Guided by quantum chemistry theory refined by highly accurate frequency-comb-assisted laser spectroscopy, record-long Rabi oscillations were demonstrated between vibrational molecular states that span the entire depth of the ground molecular potential. Enabled by the narrow molecular clock linewidth, hertz-level frequency shifts were resolved, facilitating the first characterization of molecular hyperpolarizability in this context. In a parallel effort, deeply bound strontium dimers are coherently created using the technique of stimulated Raman adiabatic passage. Ultracold collisions of alkaline-earth metal molecules in the absolute ground state are studied for the first time, revealing inelastic losses at the universal rate. This thesis reports one of the most accurate measurement of a molecule's vibrational transition frequency to date, which may potentially serve as a secondary representation of the SI unit of time in the terahertz (THz) band where standards are scarce. The prototypical molecular clock lays the important groundwork for future explorations into THz metrology, quantum chemistry, and fundamental interactions at atomic length scales.

This dissertation reports on the investigation of two-photon absorption (2PA) in a series of fluorenyl molecules. Several current and emerging technologies exploit this optical nonlinearity including two-photon fluorescence imaging, three-dimensional microfabrication, site-specific photodynamic cancer therapy and biological caging studies. The two key features of this nonlinearity which make it an ideal candidate for the above applications are its quadratic dependence on the incident irradiance and the improved penetration into absorbing media that it affords. As a consequence of the burgeoning field which exploits 2PA, it is a goal to find materials that exhibit strong two-photon absorbing capabilities. Organic materials are promising candidates for 2PA applications because their material properties can be tailored through molecular engineering thereby facilitating optimization of their nonlinear optical properties. Fluorene derivatives are particularly interesting since they possess high photochemical stability for organic molecules and are generally strongly fluorescent. By systematically altering the structural properties in a series of fluorenyl molecules, we have determined how these changes affect their two-photon absorbing capabilities. This was accomplished through characterization of both the strength and location of their 2PA spectra. In order to ensure the validity of these results, three separate nonlinear characterization techniques were employed: two-photon fluorescence spectroscopy, white-light continuum pump-probe spectroscopy, and the Z-scan technique. In addition, full linear spectroscopic characterization was performed on these molecules along with supplementary quantum chemical calculations to obtain certain molecular properties that might impact the nonlinearity. Different designs in chemical architecture allowed investigation of the effects of symmetry, solvism, donor-acceptor strengths, conjugation length, and multi-branched geometries on the two-photon absorbing properties of these molecules. In addition, the means to enhance 2PA via intermediate state resonances was investigated. To provide plausible explanations for the experimentally observed trends, a conceptually simple three level model was employed. The subsequent correlations found between chemical structure and the linear and nonlinear optical properties of these molecules provided definitive conclusions on how to properly optimize their two-photon absorbing capabilities. The resulting large nonlinearities found in these molecules have already shown promise in a variety of the aforementioned applications.

Nanoscale structures play a fundamental role in diverse scientific areas, including biology and information technology. It is necessary to develop methods that can observe nanoscale structures and dynamic processes that involve them. Colloidal plasmonic nanoparticles (plasmonic “atoms”) and their clusters (plasmonic “molecules”) are nanoscale objects with remarkable optical properties that provide new opportunities for sensing and imaging on the relevant length and time scales. Many biology questions require optically monitoring of the dynamic behavior of biological systems on single molecule level. In contrast to the commonly used fluorescent probes which have the problem of bleaching, blinking and relatively weak signals, plasmonic probes display superb brightness, persistency and photostability, thus enable long observation time and high temporal and spacial resolutions. When plasmonic atoms are clustered together, their resonances redshift while the intensities increase as a result of plasmon coupling. These optical responses are dependent on the interparticle gaps and the overall geometry, which makes plasmonic molecules capable of detecting biomolecule clustering and measuring nanometer scale distance fluctuations. In this dissertation, individual plasmonic atoms are firstly evaluated as imaging probe and their interactions with lipid membrane are tested on a newly developed on-chip black lipid membrane system. Subsequently, plasmonic dimers (plasmon rulers) prepared through DNA-programmed self-assembly are monitored to detect the mechanical properties of single biopolymers. Measurement of the spring constant of short (tens of nucleotides or base pairs) DNAs is demonstrated through plasmon coupling microscopy. Colloidal plasmonic atoms of various materials, sizes and shapes scatter vivid colors in the full-visible range. Assembling them into plasmonic molecules provides additional degrees of freedom for color manipulation. More importantly, the electric field in the gaps of plasmonic molecules can be enhanced by several orders of magnitude, which is highly desirable in single molecule sensing applications. In this dissertation, the fundamentals of plasmonic coupling are investigated through one-dimensional gold nanosphere chains. Using the directed self-assembly approach, multichromatic color-switchable plasmonic nanopixels composed of plasmonic atoms and molecules of various materials, sizes, shapes and geometries are integrated in one image with nanometer precision, which facilitates the encoding of complex spectral features with high relevance in security tagging and high density optical data storage. / 2017-01-01T00:00:00Z

We discuss the physical problem of a molecule interacting with an electromagnetic field pulse and model the problem using a time-dependent perturbation of the Born-Oppenheimer approximation to the Schrodinger equation. Using previous results that develop asymptotic series solutions in the Born-Oppenheimer parameter ε, we derive a formal Dyson series expansion in the perturbation parameter μ, which is proportional to the electromagnetic field strength. We then prove that this series is asymptotically accurate in both parameters, provided that the Hamiltonian for the electrons has purely discrete spectrum. Under more general hypotheses, we show that the series is accurate to first order in μ, and that it is accurate to one higher order if we place conditions on the abruptness of the EM pulse. We also show how this series development provides a justification for the Franck-Condon factors in the case of a diatomic molecule. / Ph. D.

Understanding structure-property relationship of molecules is imperative for designing efficient materials for organic semiconductors. Organic semiconductors are based on π-conjugated molecules, either small molecules or macromolecules such as dendrimers or polymers. Charge transport through organic materials is one of the most important processes that drive organic electronic devices. We have investigated the charge transport properties in various molecular designs based on dendrons, dendron-rod-coil molecular triads, and conjugated oligomers. The charge transport properties were studied using bottom contact field effect transistors, in which the material was deposited by spin coating. In case of dendrons, their generation and density of charge transporting functionalities were found to play a significant role in influencing the charge transport properties. In case of macromolecules such as dendron-rod-coil molecules, the solid state morphology plays a significant role in influencing the charge transport properties. While these molecules exhibit only electron transporting behavior in field-effect transistor measurements, ambipolar charge transport is observed in the diode configuration. Short conjugated oligomers, based on donor-acceptor-donor design, provide model systems for conjugated polymers. Effect of varying the donor functionality on optoelectronic and charge transport properties was studied in short donor-acceptor-donor molecules. While donor-acceptor-donor molecules are well known in the literature, the effect of molecular composition on the charge transport properties is not well understood. We designed molecules with 2,1,3-benzothiadiazole as the acceptor and thiophene based donor functionalities. These molecules exhibit a reduced bandgap, good solution processability and charge mobility making them interesting systems for application in organic photovoltaics. Cyclopentadithiophene (CPD) based materials have been widely utilized as organic semiconductors due to their planar nature which favors intermolecular charge transport. While most CPD based materials are hole transporting, incorporation of electron withdrawing fluorinated substituents imparts n-type behavior to these molecules. This change in charge transport properties has often been attributed to the lowering of the LUMO energy level due to the increased electron affinity in the molecule. We designed CPD based semiconductors in which the bridgehead position was functionalized with electron withdrawing ketone or dicyanomethylene group and the -positions were substituted with phenyl or pentafluorophenyl groups. Both the phenyl substituted molecules are p-type materials, even though the dicyanomethylene group lowers the LUMO by 500 meV as compared to the carbonyl compound. The pentafluorophenyl substituted molecules are n-type materials even as their LUMO energy levels are about 300 meV higher than the corresponding phenyl substituted molecules. This indicates that charge transport behavior is not an exclusive function of the frontier orbital energy levels.