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Thesis advisor: Eranthie Weerapana / This thesis includes two projects: “Bacteria-selective borono-peptides” and “A split ligand for lanthanide binding: facile evaluation of dimerizing proteins”. In both projects, de novo designed molecules were synthesized, optimized and incorporated into peptides. These synthetic molecular tools allow selective targeting of bacterial cell membranes and analyzing the dynamic associations of membrane-embedded proteins. 1. Bacteria-selective borono-peptides As the antibiotic resistance continues to grow, bacterial infection becomes one of the major threats to global public health. Currently, almost all the bacteria targeting strategies employ non-covalent driving forces, including charge-charge interactions, hydrophobic interactions and the formation of hydrogen bonds, to achieve bacterial selectivity. Towards novel bacteria targeting molecules, we have recruited reversible covalent chemistry in the development of bacteria-selective peptides. Targeting the diol-rich environment of a bacterial surface, we have designed and synthesized several unnatural amino acids that contain boronic acid moieties. Taking advantage of the boronic acid-diol reaction and multivalency effect, our borono-peptides are found to selectively recognize bacteria over mammalian cells. The sensitivity of the binding event to carbohydrate competitors gives a safe and facile approach to regulate molecular association with bacterial cells. This design may find applications in the fields of bacterial detection, imaging and antimicrobial drug delivery. 2. A split ligand for lanthanide binding: facile evaluation of dimerizing proteins Protein dimerization is a ubiquitous phenomenon in biology and plays a critical role in transcription regulations and various signaling processes. Methods that allow facile detection and quantification of protein dimers are highly desirable for evaluating protein dimerization in physiology and disease. Meanwhile, luminescence of lanthanides is attractive for biological applications due to its long lifetime and sharp emission profiles. We have developed a split lanthanide binding ligand that allows facile evaluation of dimerizing proteins. The fast lanthanide–ligand (dis)association allows us to monitor the dynamic behavior of dimerizing proteins. We have demonstrated the successful application of our assay on both soluble and transmembrane proteins in complex biological milieu. The split lanthanide ligand is cysteine reactive, and therefore should be readily applicable to a variety of proteins of interest. / Thesis (PhD) — Boston College, 2015. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis--University of California, Berkeley. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 242-250).

There continue to be great strides in the field of proteomics but as samples become more complex, the ability to increase sequence coverage and confidence in the identification becomes more important. Several methods of derivatization have been developed that can be used in combination with tandem mass spectrometry to identify and characterize proteins. Three types of activation, including infrared multiphoton dissociation, ultraviolet photodissociation, and electron transfer dissociation, are enhanced in this dissertation and compared to the conventional method of collisional induced dissociation (CID) to demonstrate the improved characterization of proteins. A free amine reactive phosphate group was synthesized and used to modify the N-terminus of digested peptides. This phosphate group absorbs at the IR wavelength of 10.6 µm as well as the Vacuum-ultraviolet (VUV) due to an aromatic group allowing modified peptides to be dissociated by infrared multi-photon dissociation (IRMPD) or ultraviolet photodissociation (UVPD) whereas peptides without this chromophore are less responsive to IR or UV irradiation. The PD spectra for these modified peptides yield simplified MS/MS spectra due to the neutralization of all N-terminal product ions from the incorporation the negatively charged phosphate moiety. This is especially advantageous for UVPD due to the great number of product ions produced due to the higher energy deposition of the UV photons. The MS/MS spectra also produce higher sequence coverage in comparison to CID of the modified or unmodified peptides due to more informative fragmentation pathways generated upon PD from secondary dissociation and an increased ion trapping mass range. IRMPD is also implemented for the first time on an orbitrap mass spectrometer to achieve high resolution analysis of IR chromophore-derivatized samples as well as top-down analysis of unmodified proteins. High resolution/high mass accuracy analysis is extremely beneficial for characterization of complex samples due to the likelihood of false positives at lower resolutions/accuracies. For electron transfer dissociation, precursor ions in higher charge states undergo more exothermic electron transfer and thus minimize non-dissociative charge reduction. In this dissertation, cysteine side chains are alkylated with a fixed charge to deliberately increase the charge states of peptides and improve electron transfer dissociation. ETD can also be used to study protein structure by derivatizing the intact structure with a hydrazone reagent. A hydrazone bond will be preferentially cleaved during ETD facilitating the recognition of any modified residues through a distinguishing ETD fragmentation spectrum. / text

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A frequency selective surface (FSS) based on switchable slots in the ground plane is presented. The switching is done using an actuating MEMS bridge over the slot. The intent is to demonstrate the control of the resonance frequency of the FSS by deflecting the bridge. It is shown that by applying a voltage between the bridge and the ground plane, the bridge displaces and changes the system capacitance which in turn changes the resonance frequency. Two analyses are presented; (1) Electromechanical analysis to show how the bridge deflects by the voltage, (2) Electromagnetic analysis to show how the resonance frequency changes by the bridge deflection. The device was fabricated and tested. The measurement results are presented for two up and down positions of the MEMS bridge to verify the correctness of the theory and design.

An inhibition-based fan effect was explored with two different negative priming tasks. Experiment 1 used a modified flanker-type colour blob task in both children and adults (Pritchard & Neumann, 2004), where two additional conditions were included (C2 and IR2). Each set of the colour blobs for the additional conditions consist of two distractor colours instead of one distractor colour. Experiment 2 used Navon’s (1977) global-local letter task, where a global letter contains one, two, or three local letters as distractors to see if an inhibitory fan effect operated on the should-be-ignored local letters. Results from both experiments did not support for the inhibition-based fan effect hypothesis. However, in line with Pritchard and Neumann (2004) and Frings et al. (2007), there was evidence for the claim that selective control mechanism are developed much earlier in young children than previously thought.

A frequency selective surface (FSS) based on switchable slots in the ground plane is presented. The switching is done using an actuating MEMS bridge over the slot. The intent is to demonstrate the control of the resonance frequency of the FSS by deflecting the bridge. It is shown that by applying a voltage between the bridge and the ground plane, the bridge displaces and changes the system capacitance which in turn changes the resonance frequency. Two analyses are presented; (1) Electromechanical analysis to show how the bridge deflects by the voltage, (2) Electromagnetic analysis to show how the resonance frequency changes by the bridge deflection. The device was fabricated and tested. The measurement results are presented for two up and down positions of the MEMS bridge to verify the correctness of the theory and design.

This thesis examines information-processing in chronic pain. "Schematic" processing is investigated selective memory for pain-related information is explored in depressed and non-depressed chronic pain patients, depressed non pain-patients and controls. A memory bias for sensory adjectives is found in the non depressed chronic pain group, while a tendency to over-recall both sensory and affective compared to neutral information is found in the depressed chronic pain group. No memory bias is observed in an acute pain group, and the implications of this are discussed. A possible cognitive avoidance mechanism is identified in depression. A questionnaire assessing beliefs about pain ("conceptual" processing) is developed and validated, and shown to differentiate between chronic pain patients and controls. The impact of two interventions for chronic pain (surgery and cognitive-behavioural management) on schematic and conceptual processing is investigated prospectively. In general the endorsement of organic beliefs decreases while the emphasis on psychological beliefs increases post-intervention. Evidence is found to suggest that surgery, but not cognitive-behavioural treatment, reverses pain-related memory biases. This is discussed in relation to changes in pain intensity. Evidence is provided to suggest that beliefs are causally related to several pain-related measures including anxiety, depression, health locus of control, cognitive coping strategies and activity levels. A word completion paradigm is employed to explore further the role of schematic processing in chronic pain, and finally, a lexical decision task is used to assess the role of word frequency effects in information-processing in chronic pain. These results suggest that memory biases in chronic pain cannot be explained by frequency effects, hence addressing the validity of the memory biases described earlier in the thesis.