This dissertation engages a very general question: what matters politically? This question is characterized as a point of heresy, as a site through which different political stances differentiate themselves from one another and account for their differences. Building on the concept of aesthetics of politics developed by Jacques Rancière, I seek to free up this concept’s critical and analytical potential by arguing that different aesthetics of politics act as prerequisites to divergent determinations of political importance. More precisely, I argue that significant formulations of how variations in distributions of political importance occur tend to presuppose particular accounts of the relationships between perception and interpretation, sensibility and understanding, or how we sense and how we make sense. While the concept of aesthetics is tied to particular histories of what has been called Western Modernity, I argue that Western political thought has been characterized by a deep concern for questions of perception since its allegedly inaugural texts in Classical Greece, and that the so-called postmodern condition continues to put into play aesthetic terms of political engagement. To test this hypothesis positing that we always already think of politics aesthetically, I map five influential aesthetics of politics: aesthetics of prevalence, aesthetics of emancipation, aesthetics of temperament, aesthetics of friction, and aesthetics of endurance. Each one is already manifold. To make sense of these multiplicities, each aesthetics of politics is studied through a fourfold engagement with the politics of one of the senses of the age-old fivefold of sight, taste, hearing, touch, and smell. The politics of each sense are engaged along a politological, an artistico-political, a polemological and a hauntological folds. I am thereby able to show the intricacies of how the problem of political importance has been and is being dealt with. / Graduate / 0615 / simonlab@uvic.ca

This dissertation engages a very general question: what matters politically? This question is characterized as a point of heresy, as a site through which different political stances differentiate themselves from one another and account for their differences. Building on the concept of aesthetics of politics developed by Jacques Rancière, I seek to free up this concept’s critical and analytical potential by arguing that different aesthetics of politics act as prerequisites to divergent determinations of political importance. More precisely, I argue that significant formulations of how variations in distributions of political importance occur tend to presuppose particular accounts of the relationships between perception and interpretation, sensibility and understanding, or how we sense and how we make sense. While the concept of aesthetics is tied to particular histories of what has been called Western Modernity, I argue that Western political thought has been characterized by a deep concern for questions of perception since its allegedly inaugural texts in Classical Greece, and that the so-called postmodern condition continues to put into play aesthetic terms of political engagement. To test this hypothesis positing that we always already think of politics aesthetically, I map five influential aesthetics of politics: aesthetics of prevalence, aesthetics of emancipation, aesthetics of temperament, aesthetics of friction, and aesthetics of endurance. Each one is already manifold. To make sense of these multiplicities, each aesthetics of politics is studied through a fourfold engagement with the politics of one of the senses of the age-old fivefold of sight, taste, hearing, touch, and smell. The politics of each sense are engaged along a politological, an artistico-political, a polemological and a hauntological folds. I am thereby able to show the intricacies of how the problem of political importance has been and is being dealt with. / Graduate / 0615 / simonlab@uvic.ca

Recent studies of the relationship between protein sequence and protein structure are reviewed. A detailed discussion of past attempts to predict the structure of a protein from its amino acid sequence, the protein folding problem, is presented and the strengths and weaknesses of these methods are examined. The root-mean-square deviation is studied and a benchmark for structural comparisons is established. A combinatorial approach to the protein folding problem is outlined and its advantages over existing methods is discussed. Specific algorithms based on the combinatorial approach are developed and applied to a variety of proteins. The success of this approach in terms of the root-mean-square deviation benchmark as well as the drawbacks of this method are presented.

Membrane proteins are essential cellular components, responsible for a wide variety of biological functions. In order to better understand such aspects of cell activity, researchers have pursued detailed structural analysis of this class of proteins. Because of the complexities in isolating and studying membrane proteins in their native environment, detergents are often employed as a membrane mimetic media. This thesis examines several features of transmembrane (TM) protein structure and folding in detergents through which we are able to gain insights into membrane protein folding, as well as explore the suitability of detergents as membrane-mimetic environments. We first compare the helix-helix association of a series of model TM sequences in a native bilayer to the corresponding association in a detergent environment. We find that while various classes of helix-helix interaction motifs are preserved in detergents, alterations in detergent solvation may, in turn, lead to altered association affinity. We further explore this phenomenon through investigation of the consequences of the insertion of a strongly polar residue into a TM segment. In these studies we find a correlation between sequence-dependent alterations in detergent solvation and predicted in vivo folding. We also extend such analyses to a variety of detergents and native TM segments, finding that native secondary structure, as it occurs in the context of a full-length protein, is generally well preserved in a variety of detergents. Finally, we assess the determinants of membrane protein folding using two-transmembrane segment constructs, in the process optimizing expression, production and characterization techniques for a diverse range of transmembrane protein sequences. Overall this thesis finds that, detergents are capable of solubilizing membrane proteins in a form suitable for in-depth structural characterization that may not be feasible in other environments. Thus, as an approximation of a native membrane, detergents are able to preserve certain features of membrane proteins such as helix-helix association and native secondary structure.

Membrane proteins are essential cellular components, responsible for a wide variety of biological functions. In order to better understand such aspects of cell activity, researchers have pursued detailed structural analysis of this class of proteins. Because of the complexities in isolating and studying membrane proteins in their native environment, detergents are often employed as a membrane mimetic media. This thesis examines several features of transmembrane (TM) protein structure and folding in detergents through which we are able to gain insights into membrane protein folding, as well as explore the suitability of detergents as membrane-mimetic environments. We first compare the helix-helix association of a series of model TM sequences in a native bilayer to the corresponding association in a detergent environment. We find that while various classes of helix-helix interaction motifs are preserved in detergents, alterations in detergent solvation may, in turn, lead to altered association affinity. We further explore this phenomenon through investigation of the consequences of the insertion of a strongly polar residue into a TM segment. In these studies we find a correlation between sequence-dependent alterations in detergent solvation and predicted in vivo folding. We also extend such analyses to a variety of detergents and native TM segments, finding that native secondary structure, as it occurs in the context of a full-length protein, is generally well preserved in a variety of detergents. Finally, we assess the determinants of membrane protein folding using two-transmembrane segment constructs, in the process optimizing expression, production and characterization techniques for a diverse range of transmembrane protein sequences. Overall this thesis finds that, detergents are capable of solubilizing membrane proteins in a form suitable for in-depth structural characterization that may not be feasible in other environments. Thus, as an approximation of a native membrane, detergents are able to preserve certain features of membrane proteins such as helix-helix association and native secondary structure.

Protein disulfide isomerases (PDIs) catalyze the oxidation and isomerization of disulfide bonds in proteins passing through the endoplasmic reticulum (ER). Although as many as 20 enzymes are classified as PDI family members, their relative contributions to protein folding have remained an open question. Additionally, Ero1 has been characterized as the ER oxidase that transfers oxidizing equivalents from oxygen to PDI enzymes. However, knockout mice lacking the mammalian Ero1 isoforms, Ero1Lα and Ero1Lβ, are viable, and the role of other potential ER oxidases in maintaining an oxidative ER environment is now an important issue. By systematic depletion of ER PDI family members and potential ER oxidases and assessment of disulfide bond formation of secreted endogenous substrates, I have outlined the functional relationships among some of these enzymes. PDI family member depletion revealed that PDI, although not essential for complete disulfide bond formation in client proteins, is the most significant catalyst of oxidative folding. In comparison, ERp57 acts preferentially on glycosylated substrates, ERp72 functions in a more supplementary capacity, and P5 has no detectable role in formation of disulfide bonds for the substrates assayed. Initially, no impact of depletion of Ero1 was observed under steady state conditions, suggesting that other oxidase systems are working in parallel to support normal disulfide bond formation. Subsequent experiments incorporating a reductive challenge revealed that Ero1 depletion produces the strongest delay in re-oxidation of the ER and oxidation of substrate. Depletion of two other potential ER oxidases, peroxiredoxin 4 (PRDX4) and Vitamin K epoxide reductase (VKOR), showed more modest effects. Upon co-depletion of Ero1 and other oxidases, additive effects were observed, culminating in cell death following combined removal of Ero1, PRDX4, and VKOR activities. These studies affirm the predominant roles of Ero1 in ER oxidation processes and, for the first time, establish VKOR as a significant contributor to disulfide bond formation.

Aluminum hexagonal honeycombs loaded in their tubular direction have extremely good mechanical properties, including high stiffness to weight and energy absorption capacities. The corresponding load-displacement curve exhibits a long plateau accompanied by small fluctuations. These fluctuations are due to the propagation of a folding front through the studied sample, which is due to the creation of folds. This plateau load makes honeycombs the perfect candidates for use as energy-dissipative devices such as bumpers. Previous studies have largely focused on the study of the plateau load with less attention given to the length of the folds. However, it will be seen that this parameter is crucial for both the complete understanding of the mechanics of the folding and the derivation of the plateau load. We present first an introduction to the thematic of honeycomb. Then, the first model focuses precisely on the fold length. Two hypotheses are considered, a correlation between elastic buckling and folding first and a local propagation of the existing fold secondly. The second hypothesis is found to be correct, and the results are good for thin foils. For thick foils, a geometric limitation occurs, which makes the results less precise. Then, we are able to use the previous kinematics for the folding and derive a new set of formulas for the plateau load. The results are compared with experimental results and past formulas, and are found to be good, especially for thin foils, where our results for the fold length are more precise.

In 1967 the US Air Force solicited proposals for ``low-disc-loading [Vertical Takeoff and Landing] configurations suitable for high speed flight.' Bell Helicopter elected to respond with a proposal after initial analysis on configurations including a stopped edgewise disc and a trail rotor. They concluded that a folding proprotor design would best meet the requirements laid forth. Initial analysis work began on this folding proprotor (stop-fold) design in the same year and concluded in 1972 with a full scale 25 foot diameter pylon and rotor assembly wind tunnel test at the NASA-Ames Large Scale Wind Tunnel. The project was concluded at this point and never resulted in a production or research aircraft. The original proposed stop-fold tiltrotor design by Bell Helicopter allowed for vertical takeoff and landing, a transition sequence rotating the pylon rotor assembly from helicopter to airplane mode, a conversion sequence during which the rotor stopped and blades folded along the pylon, and a transition from prop thrust to auxiliary jet engine power while the rotor was being stopped. This configuration effectively removes the high-speed restraints typical of a prop-driven aircraft and instead opens a flight envelope comparable to a fixed-wing jet. This project entails both the simulation and basic analysis of the stop-fold concept with special attention to frequency responses and potential coupling between modes.

RNA tetraloop is the smallest, simplest and the most frequent motif which is involved in numerous important biological functions. A local deviation from the RNA standard tetraloop, d2 tetraloop, has been identified with high abundance in 5S, 16S and 23S rRNAs. The presence of d2 tetraloops in highly conserved regions of 16S and 23S rRNAs suggests their functional importance. With one less residue in the loop, d2 tetraloops are considered more energetically restrained and less stable than standard tetraloops. The deletion at position j+2 in the loop is always correlated with adjacent stem distortion. MD simulations of 314-d2-tetraloop (a sample structure of d2 tetraloops) and cutd2-tetraloop (an artificially built perfect d2 tetraloop with no stem defects) have shown that stem defects are the stabilizing factor of d2 tetraloops. Simulations have also revealed that the insertion residue 318C (an example of stem defect) is stabilizing 314-d2-tetraloop by forming hydrogen bonding interactions with both the loop and the stem. When these two hydrogen bonding interactions are eliminated, the structure remained relatively stable compared to cutd2-tetraloop where the insertion residue was completely removed from the stem. This suggests the insertion residue is also stabilizing 314-d2-tetraloop by providing some conformational relaxation in the stem. Investigation of RNA standard tetraloop high temperature unfolding has revealed that the d2 tetraloop is possibly a kinetically trapped intermediate state during the folding of the standard tetraloop. High temperature unfolding simulations of standard tetraloop have shown a three-state folding behavior: a folded state, an intermediate state and an unfolded state. The folding of standard tetraloop starts with the formation of the loop. The closing base pair forms first, followed by the loop and the stem which form critical interactions such as base pairing and stacking that make a tetraloop. ROMP PNB has been investigated as supports to immobilize homogeneous catalysts to achieve both high reactivity and selectivity and easy separation. Polymers with intermediate conformational order can increase the accessibility of tethered homogeneous catalysts. Simulations of ROMP PNBDC_UD have shown the importance of bulky side groups in enabling the polymer to adopt a helical conformation. Such helical conformations have been associated with intermediate structural order in similar polymers such as PNB made by non-ROMP mechanisms. This intermediate order manifests itself as a split in the amorphous halo of WAXD pattern. Bulk simulations generated WAXD patterns that are close to the experimentally generated WAXD patterns where there are two split peaks: lower angle peak representing intermolecular interaction and higher angle peak representing intramolecular interaction.

In this thesis we present computer modelling studies that were implemented to investigate protein behavior in various environments causing their folding, unfolding and aggregation. Applications related to two important proteins - insulin and apolipoprotein C-II (ApoC-II) are presented. The use of atomistic simulation methodologies based on empirical force fields has enhanced our understanding of many physical processes governing protein structure and dynamics. However, the force fields used in classical modelling studies are often designed for a particular class of proteins and rely on continuous improvement and validation by comparison of simulations with experimental data. In Chapter 4 we present a comprehensive comparison of five popular force fields for simulation of insulin. The effect of each force field on the conformational evolution and structural properties of the protein is analysed in detail and compared with available experimental data. A fundamental phenomenon in nature is the ability of proteins to fold ab initio to their functional native conformation, also known as their biologically active state. Due to the heterogeneity and dimensionality of the systems involved, it is necessary to employ methodologies capable of accelerating rare events, specifically, configurational changes that involve the crossing of large free energy barriers. In Chapter 5, using the recently developed method BE-META we were able to identify the structural transitions and possible folding pathways of insulin. Another interesting phenomenon is the misfolding of proteins causing their aggregation, that may lead to formation of either amorphous compounds or structures of elongated-unbranched morphology known as amyloid fibrils. The deposition of amyloid fibrils in the human body may cause many debilitating diseases such as Alzheimer's and variant Creutzfeldt-Jakob diseases, thus making this field of research important and urgent. The human plasma protein apoC-II serves important roles in lipid transport, and it has been shown to form amyloid-like aggregates in solution. We have performed computational studies to investigate the effect of mutations, such as Met oxidation and the residue substitutions to hydrophobic Val and hydrophilic Gln, on dynamics of apoC-II(60-70) peptide. The conformation features relevant to the amyloidogenic propensities of the peptide were identified and presented in Chapter 6. The involvement of lipids at the various stages of development of amyloid diseases is becoming more evident in recent research efforts. In particular, micellar and sub-micellar concentrations have showed to have different effect on fibril growth and kinetics of native apoC-II and derived peptides. In Chapter 7 we investigated the influences of phospholipids at various concentrations on the structure of apoC-II(60-70) using MD and umbrella sampling methods. The molecular mechanisms of lipid effects on the peptide conformation and dynamics were identified. In Chapter 8 preliminary results on the structural stability of pre-formed oligomeric composites of apoC-II(60-70) peptide of different sizes and arrangements were also presented. The effects of mutation (oxidised Met, Met60Val and Met60Gln) on the most stable cluster was also investigated. To conclude, several ideas for continuation of research in the protein folding and aggregation field are discussed in the Future Work section of this thesis.