Essays in revealed preference theory and behavioral economics

Time, risk, and attention are all integral to economic decision making. The aim of this work is to understand those key components of decision making using a variety of approaches: providing axiomatic characterizations to investigate time discounting, generating measures of visual attention to infer consumers' intentions, and examining data from unique field settings.

Chapter 2, co-authored with Federico Echenique and Kota Saito, presents the first revealed-preference characterizations of exponentially-discounted utility model and its generalizations. My characterizations provide non-parametric revealed-preference tests. I apply the tests to data from a recent experiment, and find that the axiomatization delivers new insights on a dataset that had been analyzed by traditional parametric methods.

Chapter 3, co-authored with Min Jeong Kang and Colin Camerer, investigates whether "pre-choice" measures of visual attention improve in prediction of consumers' purchase intentions. We measure participants' visual attention using eyetracking or mousetracking while they make hypothetical as well as real purchase decisions. I find that different patterns of visual attention are associated with hypothetical and real decisions. I then demonstrate that including information on visual attention improves prediction of purchase decisions when attention is measured with mousetracking.

Chapter 4 investigates individuals' attitudes towards risk in a high-stakes environment using data from a TV game show, Jeopardy!. I first quantify players' subjective beliefs about answering questions correctly. Using those beliefs in estimation, I find that the representative player is risk averse. I then find that trailing players tend to wager more than "folk" strategies that are known among the community of contestants and fans, and this tendency is related to their confidence. I also find gender differences: male players take more risk than female players, and even more so when they are competing against two other male players.

Chapter 5, co-authored with Colin Camerer, investigates the dynamics of the favorite-longshot bias (FLB) using data on horse race betting from an online exchange that allows bettors to trade "in-play." I find that probabilistic forecasts implied by market prices before start of the races are well-calibrated, but the degree of FLB increases significantly as the events approach toward the end.

Mechanistic and kinetic studies of the surface chemistry of iridium and ruthenium

Quantitative investigations of the mechanisms and the kinetics of the surface-catalyzed activation of C-H, N-H, C-C, and C-N bonds on the close-packed surfaces of Ir(111) and Ru(001) have been performed. The interaction of CH_3NH_2 with Ru(001) was investigated in ultrahigh vacuum with the techniques of high-resolution electron energy loss spectroscopy and thermal desorption mass spectrometry. Activation of the central C-N bond is observed, but it is less favored than the competing channel of complete dehydrogenation, by a ratio between 2:1 to 3:1. The decomposition mechanism has been characterized with several surface intermediates and gas-phase products identified. A pronounced preference for the activation of C-H over N-H and C-N bonds has been established. Additionally, the kinetics of the initial dissociation of short chain alkanes on Ir(111) has been examined, and the rate parameters of the activation of C-C bonds and primary, secondary, and tertiary C-H bonds have been determined. The formation of primary alkyl products is favored, over most of the experimental temperature range, despite the thermodynamic preference for the activation of individual secondary and tertiary C-H bonds in comparison to individual primary C-H bonds. At higher surface temperatures, the activation of C-C bonds occurs at competitive rates to the C-H reaction channel. The measured deuterium kinetic isotope effect implicates substantial deformation of the terminal methyl group in the transition state of C-C bond cleavage. Finally, the surface structure sensitivity of C-H bond cleavage has been quantified for smooth (111) and corrugated (110) surfaces of iridium and platinum, as well as for step edge defect sites on Ir(111).

Synthetic, kinetic and mechanistic studies in early transition metal systems. I. α- and β-hydrogen elimination reactions in derivatives of permethyltitanocene, -zirconocene, and -hafnocene. II. The reactions of aluminum alkyls with derivatives of permethylniobocene

The thermal decomposition of Cp*Ti(CH_3)_2 (Cp*≡ ƞ^5-C_5Me_5) toluene solution follows cleanly first-order kinetics and produces a single titanium product Cp*(C_5Me_4CH_2)Ti(CH_3) concurrent with the evolution of one equivalent of methane. Labeling studies using Cp*_2Ti- (CD_3)_2 and (Cp*-d_(15))_2Ti(CH_3)_2 show the decomposition to be intramolecular and the methane to be produced by the coupling of a methyl group with a hydrogen from the other TiCH_3 group. Activation parameters, ΔH^‡ and ΔS^‡, and kinetic deuterium isotope effects have been measured. The alternative decomposition pathways of α-hydrogen abstraction and a-hydrogen elimination, both leading to a titanium-methylidene intermediate, are discussed.

The insertion of unactivated acetylenes into the metal-hydride bonds of Cp*_2MH_2 (M = Zr, Hf) proceeds rapidly at low temperature to form monoand/ or bisinsertion products, dependent upon the steric bulk of the acetylene substituents. Cp*_2M(H)(C(Me)=CHMe), Cp*_2M(H)(CH=CHCMe_3), Cp*_2M(H)-(CH=CHPh), Cp*_2M(CH=CHPh)_2, Cp*_2M(CH=CHCH_3)_2 and Cp*_2Zr- (CH=CHCH_2CH_3)_2 have been isolated and characterized. To extend the study of unsaturated-carbon ligands, Cp*_2M(C≡CCH_3)_2 have been prepared by treating Cp*_2MCl_2 with LiC≡CCH_3. The reactivity of many of these complexes with carbon monoxide and dihydrogen is surveyed. The mono(2- butenyl) complexes Cp*_2M(H)(C(Me)=CHMe) rearrange at room temperature, forming the crotyl-hydride species Cp*_2M(H)(ƞ^3-C_4H_7). The bis(propenyl) and bis(l-butenyl) zirconium complexes Cp*_2Zr(CH=CHR)_2 (R = CH_3, CH_2CH_3) also rearrange, forming zirconacyclopentenes. Labeling studies, reaction chemistry, and kinetic measurements, including deuterium isotope effects, demonstrate that the unusual 6-hydrogen elimination from an sp^2-hybridized carbon is the first step in these latter rearrangements but is not observed in the former. Details of these mechanisms and the differences in reactivity of the zirconium and hafnium complexes are discussed.

The reactions of hydride- and alkyl-carbonyl derivatives of permethylniobocene with equimolar amounts of trialkylaluminum reagents occur rapidly producing the carbonyl adducts Cp*_2Nb(R)(COAlR'_3) (R = H, CH_3, CH_2CH_3, CH_2CH_2Ph, C(Me)=CHMe; R' = Me, Et). The hydride adduct Cp*_2NbH_3•AlEt_3 has also been formed. In solution, each of these compounds exists in equilibrium with the uncomplexed species. The formation constants for Cp*_2Nb(H)(COA1R'_R) have been measured. They indicate the steric bulk of the Cp* ligands plays a deciding factor in the isolation of the first example of an aluminum Lewis acid bound to a carbonyl-oxygen in preference to a metalhydride. Reactions of Cp*_2Nb(H)CO with other Lewis acids and of the one:one adducts with H_2, CO and C_2H_4 are also discussed.

Cp*_2Nb(H)(C_2H_4) also reacts with equimolar amounts of trialkylaluminum reagents, forming a one:one complex that ^1H NMR spectroscopy indicates contains a Nb-CH_2CH_2-Al bridge. This adduct also exists in equilibrium with the uncomplexed species in solution. The formation constant for Cp*_2N+/b(H)(CH_2CH_2ĀlEt_3) has been measured. Reactions of Cp*_2Nb(H)(C_2H_4) with other Lewis acids and the reactions of Cp*_2N+b(H)- (CH_2CH_2ĀlEt_3) with CO and C_2H_4 are described, as are the reactions of Cp_*2Nb(H)(CH_2=CHR) (R = Me, Ph), Cp*_2Nb(H)(CH_3C≡CCH_3) and Cp*_2Ti-(C_2H_4) with AlEt_3.

Optimal design of building structures using genetic algorithms

A general framework for multi-criteria optimal design is presented which is well-suited for automated design of structural systems. A systematic computer-aided optimal design decision process is developed which allows the designer to rapidly evaluate and improve a proposed design by taking into account the major factors of interest related to different aspects such as design, construction, and operation.

The proposed optimal design process requires the selection of the most promising choice of design parameters taken from a large design space, based on an evaluation using specified criteria. The design parameters specify a particular design, and so they relate to member sizes, structural configuration, etc. The evaluation of the design uses performance parameters which may include structural response parameters, risks due to uncertain loads and modeling errors, construction and operating costs, etc. Preference functions are used to implement the design criteria in a "soft" form. These preference functions give a measure of the degree of satisfaction of each design criterion. The overall evaluation measure for a design is built up from the individual measures for each criterion through a preference combination rule. The goal of the optimal design process is to obtain a design that has the highest overall evaluation measure - an optimization problem.

Genetic algorithms are stochastic optimization methods that are based on evolutionary theory. They provide the exploration power necessary to explore high-dimensional search spaces to seek these optimal solutions. Two special genetic algorithms, hGA and vGA, are presented here for continuous and discrete optimization problems, respectively.

The methodology is demonstrated with several examples involving the design of truss and frame systems. These examples are solved by using the proposed hGA and vGA.

Voting games with incomplete information

We examine voting situations in which individuals have incomplete information over each others' true preferences. In many respects, this work is motivated by a desire to provide a more complete understanding of so-called probabilistic voting.

Chapter 2 examines the similarities and differences between the incentives faced by politicians who seek to maximize expected vote share, expected plurality, or probability of victory in single member: single vote, simple plurality electoral systems. We find that, in general, the candidates' optimal policies in such an electoral system vary greatly depending on their objective function. We provide several examples, as well as a genericity result which states that almost all such electoral systems (with respect to the distributions of voter behavior) will exhibit different incentives for candidates who seek to maximize expected vote share and those who seek to maximize probability of victory.

In Chapter 3, we adopt a random utility maximizing framework in which individuals' preferences are subject to action-specific exogenous shocks. We show that Nash equilibria exist in voting games possessing such an information structure and in which voters and candidates are each aware that every voter's preferences are subject to such shocks. A special case of our framework is that in which voters are playing a Quantal Response Equilibrium (McKelvey and Palfrey (1995), (1998)). We then examine candidate competition in such games and show that, for sufficiently large electorates, regardless of the dimensionality of the policy space or the number of candidates, there exists a strict equilibrium at the social welfare optimum (i.e., the point which maximizes the sum of voters' utility functions). In two candidate contests we find that this equilibrium is unique.

Finally, in Chapter 4, we attempt the first steps towards a theory of equilibrium in games possessing both continuous action spaces and action-specific preference shocks. Our notion of equilibrium, Variational Response Equilibrium, is shown to exist in all games with continuous payoff functions. We discuss the similarities and differences between this notion of equilibrium and the notion of Quantal Response Equilibrium and offer possible extensions of our framework.

Ancillary ligand effects : from zirconium(IV)-catalyzed homogeneous propylene polymerization to platinum(II)-mediated C-H bond activation

A series of C_s- and C₁-symmetric doubly-linked ansa-metallocenes of the general formula {1,1'-SiMe₂-2,2'-E-('ƞ⁵-C₅H₂-4-R¹)-(ƞ⁵-C₅H-3',5'-(CHMe₂)₂)}ZrC₂ (E = SiMe₂ (1), SiPh₂ (2), SiMe₂ -SiMe₂ (3); R¹ = H, CHMe₂, C₅H₉, C₆H₁₁, C₆H₅) has been prepared. When activated by methylaluminoxane, these are active propylene polymerization catalysts. 1 and 2 produce syndiotactic polypropylenes, and 3 produces isotactic polypropylenes. Site epimerization is the major pathway for stereoerror formation for 1 and 2. In addition, the polymer chain has slightly stronger steric interaction with the diphenylsilylene linker than with the dimethylsilylene linker. This results in more frequent site epimerization and reduced syndiospecificity for 2 compared to 1.

C₁-Symmetric ansa-zirconocenes [1,1 '-SiMe₂-(C₅H₄)-(3-R-C₅H₃)]ZrCl₂ (4), [1,1 '-SiMe₂-(C₅H₄)-(2,4-R₂-C₅H₂)]ZrCl₂ (5) and [1,1 '-SiMe₂-2,2 '-(SiMe₂-SiMe₂)-(C₅H₃)-( 4-R-C₅H₂)]ZrCl₂ (6) have been prepared to probe the origin of isospecificity in 3. While 4 and 3 produce polymers with similar isospecificity, 5 and 6 give mostly hemi-isotactic-like polymers. It is proposed that the facile site epimerization via an associative pathway allows rapid equilibration of the polymer chain between the isospecific and aspecific insertion sites. This results in more frequent insertion from the isospecific site, which has a lower kinetic barrier for chain propagation. On the other hand, site epimerization for 5 and 6 is slow. This leads to mostly alternating insertion from the isospecific and aspecific sites, and consequently, a hemi-isotactic-like polymers. In comparison, site epimerization is even slower for 3, but enchainment from the aspecific site has an extremely high kinetic barrier for monomer coordination. Therefore, enchainment occurs preferentially from the isospecific site to produce isotactic polymers.

A series of cationic complexes [(ArN=CR-CR=NAr)PtMe(L)]⁺[BF₄]⁺ (Ar = aryl; R = H, CH₃; L = water, trifluoroethanol) has been prepared. They react smoothly with benzene at approximately room temperature in trifluoroethanol solvent to yield methane and the corresponding phenyl Pt(II) cations, via Pt(IV)-methyl-phenyl-hydride intermediates. The reaction products of methyl-substituted benzenes suggest an inherent reactivity preference for aromatic over benzylic C-H bond activation, which can however be overridden by steric effects. For the reaction of benzene with cationic Pt(II) complexes, in which the diimine ligands bear 3,5-disubstituted aryl groups at the nitrogen atoms, the rate-determining step is C-H bond activation. For the more sterically crowded analogs with 2,6-dimethyl-substituted aryl groups, benzene coordination becomes rate-determining. The more electron-rich the ligand, as reflected by the CO stretching frequency in the IR spectrum of the corresponding cationic carbonyl complex, the faster the rate of C-H bond activation. This finding, however, does not reflect the actual C-H bond activation process, but rather reflects only the relative ease of solvent molecules displacing water molecules to initiate the reaction. That is, the change in rates is mostly due to a ground state effect. Several lines of evidence suggest that associative substitution pathways operate to get the hydrocarbon substrate into, and out of, the coordination sphere; i.e., that benzene substitution proceeds by a solvent- (TFE-) assisted associative pathway.

Efficient methods for empirical tests of behavioral economics theories in laboratory and field experiments

In the quest for a descriptive theory of decision-making, the rational actor model in economics imposes rather unrealistic expectations and abilities on human decision makers. The further we move from idealized scenarios, such as perfectly competitive markets, and ambitiously extend the reach of the theory to describe everyday decision making situations, the less sense these assumptions make. Behavioural economics has instead proposed models based on assumptions that are more psychologically realistic, with the aim of gaining more precision and descriptive power. Increased psychological realism, however, comes at the cost of a greater number of parameters and model complexity. Now there are a plethora of models, based on different assumptions, applicable in differing contextual settings, and selecting the right model to use tends to be an ad-hoc process. In this thesis, we develop optimal experimental design methods and evaluate different behavioral theories against evidence from lab and field experiments.

We look at evidence from controlled laboratory experiments. Subjects are presented with choices between monetary gambles or lotteries. Different decision-making theories evaluate the choices differently and would make distinct predictions about the subjects' choices. Theories whose predictions are inconsistent with the actual choices can be systematically eliminated. Behavioural theories can have multiple parameters requiring complex experimental designs with a very large number of possible choice tests. This imposes computational and economic constraints on using classical experimental design methods. We develop a methodology of adaptive tests: Bayesian Rapid Optimal Adaptive Designs (BROAD) that sequentially chooses the "most informative" test at each stage, and based on the response updates its posterior beliefs over the theories, which informs the next most informative test to run. BROAD utilizes the Equivalent Class Edge Cutting (EC²) criteria to select tests. We prove that the EC² criteria is adaptively submodular, which allows us to prove theoretical guarantees against the Bayes-optimal testing sequence even in the presence of noisy responses. In simulated ground-truth experiments, we find that the EC² criteria recovers the true hypotheses with significantly fewer tests than more widely used criteria such as Information Gain and Generalized Binary Search. We show, theoretically as well as experimentally, that surprisingly these popular criteria can perform poorly in the presence of noise, or subject errors. Furthermore, we use the adaptive submodular property of EC² to implement an accelerated greedy version of BROAD which leads to orders of magnitude speedup over other methods.

We use BROAD to perform two experiments. First, we compare the main classes of theories for decision-making under risk, namely: expected value, prospect theory, constant relative risk aversion (CRRA) and moments models. Subjects are given an initial endowment, and sequentially presented choices between two lotteries, with the possibility of losses. The lotteries are selected using BROAD, and 57 subjects from Caltech and UCLA are incentivized by randomly realizing one of the lotteries chosen. Aggregate posterior probabilities over the theories show limited evidence in favour of CRRA and moments' models. Classifying the subjects into types showed that most subjects are described by prospect theory, followed by expected value. Adaptive experimental design raises the possibility that subjects could engage in strategic manipulation, i.e. subjects could mask their true preferences and choose differently in order to obtain more favourable tests in later rounds thereby increasing their payoffs. We pay close attention to this problem; strategic manipulation is ruled out since it is infeasible in practice, and also since we do not find any signatures of it in our data.

In the second experiment, we compare the main theories of time preference: exponential discounting, hyperbolic discounting, "present bias" models: quasi-hyperbolic (α, β) discounting and fixed cost discounting, and generalized-hyperbolic discounting. 40 subjects from UCLA were given choices between 2 options: a smaller but more immediate payoff versus a larger but later payoff. We found very limited evidence for present bias models and hyperbolic discounting, and most subjects were classified as generalized hyperbolic discounting types, followed by exponential discounting.

In these models the passage of time is linear. We instead consider a psychological model where the perception of time is subjective. We prove that when the biological (subjective) time is positively dependent, it gives rise to hyperbolic discounting and temporal choice inconsistency.

We also test the predictions of behavioral theories in the "wild". We pay attention to prospect theory, which emerged as the dominant theory in our lab experiments of risky choice. Loss aversion and reference dependence predicts that consumers will behave in a uniquely distinct way than the standard rational model predicts. Specifically, loss aversion predicts that when an item is being offered at a discount, the demand for it will be greater than that explained by its price elasticity. Even more importantly, when the item is no longer discounted, demand for its close substitute would increase excessively. We tested this prediction using a discrete choice model with loss-averse utility function on data from a large eCommerce retailer. Not only did we identify loss aversion, but we also found that the effect decreased with consumers' experience. We outline the policy implications that consumer loss aversion entails, and strategies for competitive pricing.

In future work, BROAD can be widely applicable for testing different behavioural models, e.g. in social preference and game theory, and in different contextual settings. Additional measurements beyond choice data, including biological measurements such as skin conductance, can be used to more rapidly eliminate hypothesis and speed up model comparison. Discrete choice models also provide a framework for testing behavioural models with field data, and encourage combined lab-field experiments.

Structure-, stereochemistry-, and metal-regulated DNA binding/cleaving molecules

In the cell, the binding of proteins to specific sequences of double helical DNA is essential for controlling the processes of protein synthesis (at the level of DNA transcription) and cell proliferation (at the level of DNA replication). In the laboratory, the sequence-specific DNA binding/cleaving properties of restriction endonuclease enzymes (secreted by microorganisms to protect them from foreign DNA molecules) have helped to fuel a revolution in molecular biology. The strength and specificity of a protein:DNA interaction depend upon structural features inherent to the protein and DNA sequences, but it is now appreciated that these features (and therefore protein:DNA complexation) may be altered (regulated) by other protein:DNA complexes, or by environmental factors such as temperature or the presence of specific organic molecules or inorganic ions. It is also now appreciated that molecules much smaller than proteins (including antibiotics of molecular weight less than 2000 and oligonucleotides) can bind to double-helical DNA in sequence-specific fashion. Elucidation of structural motifs and microscopic interactions responsible for the specific molecular recognition of DNA leads to greater understanding of natural processes and provides a basis for the design of novel sequence-specific DNA binding molecules. This thesis describes the synthesis and DNA binding/cleaving characteristics of molecules designed to probe structural, stereochemical, and environmental factors that regulate sequence-specific DNA recognition.

Chapter One introduces the DNA minor groove binding antibiotics Netropsin and Distamycin A, which are di- and tri(N-methylpyrrolecarboxamide) peptides, respectively. The method of DNA affinity cleaving, which has been employed to determine DNA binding properties of designed synthetic molecules is described. The design and synthesis of a series of Netropsin dimers linked in tail-to-tail fashion (by oxalic, malonic, succinic, or fumaric acid), or in head-to-tail fashion (by glycine, β-alanine, and γ-aminobutanoic acid (Gaba)) are presented. These Bis(Netropsin)s were appended with the iron-chelating functionality EDTA in order to make use of the technique of DNA affinity cleaving. Bis(Netropsin)-EDTA compounds are analogs of penta(N-methylpyrrolecarboxamide)-EDTA (P5E), which may be considered a head-to-tail Netropsin dimer linked by Nmethylpyrrolecarboxamide. Low- and high-resolution analysis of pBR322 DNA affinity cleaving by the iron complexes of these molecules indicated that small changes in the length and nature of the linker had significant effects on DNA binding/cleaving efficiency (a measure of DNA binding affinity). DNA binding/cleaving efficiency was found to decrease with changes in the linker in the order β-alanine > succinamide > fumaramide > N-methylpyrrolecarboxamide > malonamide >glycine, γ-aminobutanamide > oxalamide. In general, the Bis(Netropsin)-EDTA:Fe compounds retained the specificity for seven contiguous A:T base pairs characteristic of P5E:Fe binding. However, Bis(Netropsin)Oxalamide- EDTA:Fe exhibited decreased specificity for A:T base pairs, and Bis(Netropsin)-Gaba-EDT A:Fe exhibited some DNA binding sites of less than seven base pairs. Bis(Netropsin)s linked with diacids have C₂-symmmetrical DNA binding subunits and exhibited little DNA binding orientation preference. Bis(Netropsin)s linked with amino acids lack C₂-symmetrical DNA binding subunits and exhibited higher orientation preferences. A model for the high DNA binding orientation preferences observed with head-to-tail DNA minor groove binding molecules is presented.

Chapter Two describes the design, synthesis, and DNA binding properties of a series of chiral molecules: Bis(Netropsin)-EDTA compounds with linkers derived from (R,R)-, (S,S)-, and (RS,SR)-tartaric acids, (R,R)-, (S,S)-, and (RS,SR)-tartaric acid acetonides, (R)- and (S)-malic acids, N ,N-dimethylaminoaspartic acid, and (R)- and (S)-alanine, as well as three constitutional isomers in which an N-methylpyrrolecarboxamide (P1) subunit and a tri(N-methylpyrrolecarboxamide)-EDTA (P3-EDTA) subunit were linked by succinic acid, (R ,R)-, and (S ,S)-tartaric acids. DNA binding/cleaving efficiencies among this series of molecules and the Bis(Netropsin)s described in Chapter One were found to decrease with changes in the linker in the order β-alanine > succinamide > P1-succinamide-P3 > fumaramide > (S)-malicamide > N-methylpyrrolecarboxamide > (R)-malicamide > malonamide > N ,N-dimethylaminoaspanamide > glycine = Gaba = (S,S)-tartaramide = P1-(S,S)-tanaramide-P3 > oxalamide > (RS,SR)-tartaramide = P1- (R,R)-tanaramide-P3 > (R,R)-tartaramide (no sequence-specific DNA binding was detected for Bis(Netropsin)s linked by (R)- or (S)-alanine or by tartaric acid acetonides). The chiral molecules retained DNA binding specificity for seven contiguous A:T base pairs. From the DNA affinity cleaving data it could be determined that: 1) Addition of one or two substituents to the linker of Bis(Netropsin)-Succinamide resulted in stepwise decreases in DNA binding affinity; 2) molecules with single hydroxyl substituents bound DNA more strongly than molecules with single dimethylamino substituents; 3) hydroxyl-substituted molecules of (S) configuration bound more strongly to DNA than molecules of (R) configuration. This stereochemical regulation of DNA binding is proposed to arise from the inherent right-handed twist of (S)-enantiomeric Bis(Netropsin)s versus the inherent lefthanded twist of (R)-enantiomeric Bis(Netropsin)s, which makes the (S)-enantiomers more complementary to the right-handed twist of B form DNA.

Chapter Three describes the design and synthesis of molecules for the study of metalloregulated DNA binding phenomena. Among a series of Bis(Netropsin)-EDTA compounds linked by homologous tethers bearing four, five, or six oxygen atoms, the Bis(Netropsin) linked by a pentaether tether exhibited strongly enhanced DNA binding/cleaving in the presence of strontium or barium cations. The observed metallospecificity was consistent with the known affinities of metal cations for the cyclic hexaether 18-crown-6 in water. High-resolution DNA affinity cleaving analysis indicated that DNA binding by this molecule in the presence of strontium or barium was not only stronger but of different sequence-specificity than the (weak) binding observed in the absence of metal cations. The metalloregulated binding sites were consistent with A:T binding by the Netropsin subunits and G:C binding by a strontium or barium:pentaether complex. A model for the observed positive metalloregulation and novel sequence-specificity is presented. The effects of 44 different cations on DNA affinity cleaving by P5E:Fe were examined. A series of Bis(Netropsin)-EDTA compounds linked by tethers bearing two, three, four, or five amino groups was also synthesized. These molecules exhibited strong and specific binding to A:T rich regions of DNA. It was found that the iron complexes of these molecules bound and cleaved DNA most efficiently at pH 6.0-6.5, while P5E:Fe bound and cleaved most efficiently at pH 7.5-8.0. Incubating the Bis(Netropsin) Polyamine-EDTA:Fe molecules with K₂PdCl₄ abolished their DNA binding/cleaving activity. It is proposed that the observed negative metalloregulation arises from kinetically inert Bis(Netropsin) Polyamine:Pd(II) complexes or aggregates, which are sterically unsuitable for DNA complexation. Finally, attempts to produce a synthetic metalloregulated DNA binding protein are described. For this study, five derivatives of a synthetic 52 amino acid residue DNA binding/cleaving protein were produced. The synthetic mutant proteins carried a novel pentaether ionophoric amino acid residue at different positions within the primary sequence. The proteins did not exhibit significant DNA binding/cleaving activity, but they served to illustrate the potential for introducing novel amino acid residues within DNA binding protein sequences, and for the development of the tricyclohexyl ester of EDTA as a superior reagent for the introduction of EDT A into synthetic proteins.

Chapter Four describes the discovery and characterization of a new DNA binding/cleaving agent, [SalenMn(III)]OAc. This metal complex produces single- and double-strand cleavage of DNA, with specificity for A:T rich regions, in the presence of oxygen atom donors such as iodosyl benzene, hydrogen peroxide, or peracids. Maximal cleavage by [SalenMn(III)]OAc was produced at pH 6-7. A comparison of DNA singleand double-strand cleavage by [SalenMn(III)]⁺ and other small molecules (Methidiumpropyl-EDTA:Fe, Distamycin-EDTA:Fe, Neocarzinostatin, Bleomycin:Fe) is presented. It was found that DNA cleavage by [SalenMn(III)]⁺ did not require the presence of dioxygen, and that base treatment of DNA subsequent to cleavage by [SalenMn(III)]⁺ afforded greater cleavage and alterations in the cleavage patterns. Analysis of DNA products formed upon DNA cleavage by [SalenMn(III)] indicated that cleavage was due to oxidation of the sugar-phosphate backbone of DNA. Several mechanisms consistent with the observed products and reaction requirements are discussed.

Chapter Five describes progress on some additional studies. In one study, the DNA binding/cleaving specificities of Distamycin-EDTA derivatives bearing pyrrole N-isopropyl substituents were found to be the same as those of derivatives bearing pyrrole N-methyl substituents. In a second study, the design of and synthetic progress towards a series of nucleopeptide activators of transcription are presented. Five synthetic plasmids designed to test for activation of in vitro run-off transcription by DNA triple helix-forming oligonucleotides or nucleopeptides are described.

Chapter Six contains the experimental documentation of the thesis work.

The Molecular Basis of Lysine Acetylation: Addition, Removal, and Recognition

Acetyltransferases and deacetylases catalyze the addition and removal, respectively, of acetyl groups to the epsilon-amino group of protein lysine residues. This modification can affect the function of a protein through several means, including the recruitment of specific binding partners called acetyl-lysine readers. Acetyltransferases, deacetylases, and acetyl-lysine readers have emerged as crucial regulators of biological processes and prominent targets for the treatment of human disease. This work describes a combination of structural, biochemical, biophysical, cell-biological, and organismal studies undertaken on a set of proteins that cumulatively include all steps of the acetylation process: the acetyltransferase MEC-17, the deacetylase SIRT1, and the acetyl-lysine reader DPF2. Tubulin acetylation by MEC-17 is associated with stable, long-lived microtubule structures. We determined the crystal structure of the catalytic domain of human MEC-17 in complex with the cofactor acetyl-CoA. The structure in combination with an extensive enzymatic analysis of MEC-17 mutants identified residues for cofactor and substrate recognition and activity. A large, evolutionarily conserved hydrophobic surface patch distal to the active site was shown to be necessary for catalysis, suggesting that specificity is achieved by interactions with the alpha-tubulin substrate that extend outside of the modified surface loop. Experiments in C. elegans showed that while MEC-17 is required for touch sensitivity, MEC-17 enzymatic activity is dispensible for this behavior. SIRT1 deacetylates a wide range of substrates, including p53, NF-kappaB, FOXO transcription factors, and PGC-1-alpha, with roles in cellular processes ranging from energy metabolism to cell survival. SIRT1 activity is uniquely controlled by a C-terminal regulatory segment (CTR). Here we present crystal structures of the catalytic domain of human SIRT1 in complex with the CTR in an apo form and in complex with a cofactor and a pseudo-substrate peptide. The catalytic domain adopts the canonical sirtuin fold. The CTR forms a beta-hairpin structure that complements the beta-sheet of the NAD^+-binding domain, covering an essentially invariant, hydrophobic surface. A comparison of the apo and cofactor bound structures revealed conformational changes throughout catalysis, including a rotation of a smaller subdomain with respect to the larger NAD^+-binding subdomain. A biochemical analysis identified key residues in the active site, an inhibitory role for the CTR, and distinct structural features of the CTR that mediate binding and inhibition of the SIRT1 catalytic domain. DPF2 represses myeloid differentiation in acute myelogenous leukemia. Finally, we solved the crystal structure of the tandem PHD domain of human DPF2. We showed that DPF2 preferentially binds H3 tail peptides acetylated at Lys14, and binds H4 tail peptides with no preference for acetylation state. Through a structural and mutational analysis we identify the molecular basis of histone recognition. We propose a model for the role of DPF2 in AML and identify the DPF2 tandem PHD finger domain as a promising novel target for anti-leukemia therapeutics.

Structural Design under Seismic Risk Using Multiple Performance Objectives

Structural design is a decision-making process in which a wide spectrum of requirements, expectations, and concerns needs to be properly addressed. Engineering design criteria are considered together with societal and client preferences, and most of these design objectives are affected by the uncertainties surrounding a design. Therefore, realistic design frameworks must be able to handle multiple performance objectives and incorporate uncertainties from numerous sources into the process.

In this study, a multi-criteria based design framework for structural design under seismic risk is explored. The emphasis is on reliability-based performance objectives and their interaction with economic objectives. The framework has analysis, evaluation, and revision stages. In the probabilistic response analysis, seismic loading uncertainties as well as modeling uncertainties are incorporated. For evaluation, two approaches are suggested: one based on preference aggregation and the other based on socio-economics. Both implementations of the general framework are illustrated with simple but informative design examples to explore the basic features of the framework.

The first approach uses concepts similar to those found in multi-criteria decision theory, and directly combines reliability-based objectives with others. This approach is implemented in a single-stage design procedure. In the socio-economics based approach, a two-stage design procedure is recommended in which societal preferences are treated through reliability-based engineering performance measures, but emphasis is also given to economic objectives because these are especially important to the structural designer's client. A rational net asset value formulation including losses from uncertain future earthquakes is used to assess the economic performance of a design. A recently developed assembly-based vulnerability analysis is incorporated into the loss estimation.

The presented performance-based design framework allows investigation of various design issues and their impact on a structural design. It is a flexible one that readily allows incorporation of new methods and concepts in seismic hazard specification, structural analysis, and loss estimation.