Protein and Drug Design Algorithms Using Improved Biophysical Modeling

This thesis focuses on the development of algorithms that will allow protein design calculations to incorporate more realistic modeling assumptions. Protein design algorithms search large sequence spaces for protein sequences that are biologically and medically useful. Better modeling could improve the chance of success in designs and expand the range of problems to which these algorithms are applied. I have developed algorithms to improve modeling of backbone flexibility (DEEPer) and of more extensive continuous flexibility in general (EPIC and LUTE). I’ve also developed algorithms to perform multistate designs, which account for effects like specificity, with provable guarantees of accuracy (COMETS), and to accommodate a wider range of energy functions in design (EPIC and LUTE).

Physical Insights, Steady Aerodynamic Effects, and a Design Tool for Low-Pressure Turbine Flutter

The successful, efficient, and safe turbine design requires a thorough understanding of the underlying physical phenomena. This research investigates the physical understanding and parameters highly correlated to flutter, an aeroelastic instability prevalent among low pressure turbine (LPT) blades in both aircraft engines and power turbines. The modern way of determining whether a certain cascade of LPT blades is susceptible to flutter is through time-expensive computational fluid dynamics (CFD) codes. These codes converge to solution satisfying the Eulerian conservation equations subject to the boundary conditions of a nodal domain consisting fluid and solid wall particles. Most detailed CFD codes are accompanied by cryptic turbulence models, meticulous grid constructions, and elegant boundary condition enforcements all with one goal in mind: determine the sign (and therefore stability) of the aerodynamic damping. The main question being asked by the aeroelastician, ``is it positive or negative?'' This type of thought-process eventually gives rise to a black-box effect, leaving physical understanding behind. Therefore, the first part of this research aims to understand and reveal the physics behind LPT flutter in addition to several related topics including acoustic resonance effects. A percentage of this initial numerical investigation is completed using an influence coefficient approach to study the variation the work-per-cycle contributions of neighboring cascade blades to a reference airfoil. The second part of this research introduces new discoveries regarding the relationship between steady aerodynamic loading and negative aerodynamic damping. Using validated CFD codes as computational wind tunnels, a multitude of low-pressure turbine flutter parameters, such as reduced frequency, mode shape, and interblade phase angle, will be scrutinized across various airfoil geometries and steady operating conditions to reach new design guidelines regarding the influence of steady aerodynamic loading and LPT flutter. Many pressing topics influencing LPT flutter including shocks, their nonlinearity, and three-dimensionality are also addressed along the way. The work is concluded by introducing a useful preliminary design tool that can estimate within seconds the entire aerodynamic damping versus nodal diameter curve for a given three-dimensional cascade.

Ground and Electronic Excited States from Pairing Matrix Fluctuation and Particle-Particle Random Phase Approximation

The accurate description of ground and electronic excited states is an important and challenging topic in quantum chemistry. The pairing matrix fluctuation, as a counterpart of the density fluctuation, is applied to this topic. From the pairing matrix fluctuation, the exact electron correlation energy as well as two electron addition/removal energies can be extracted. Therefore, both ground state and excited states energies can be obtained and they are in principle exact with a complete knowledge of the pairing matrix fluctuation. In practice, considering the exact pairing matrix fluctuation is unknown, we adopt its simple approximation --- the particle-particle random phase approximation (pp-RPA) --- for ground and excited states calculations. The algorithms for accelerating the pp-RPA calculation, including spin separation, spin adaptation, as well as an iterative Davidson method, are developed. For ground states correlation descriptions, the results obtained from pp-RPA are usually comparable to and can be more accurate than those from traditional particle-hole random phase approximation (ph-RPA). For excited states, the pp-RPA is able to describe double, Rydberg, and charge transfer excitations, which are challenging for conventional time-dependent density functional theory (TDDFT). Although the pp-RPA intrinsically cannot describe those excitations excited from the orbitals below the highest occupied molecular orbital (HOMO), its performances on those single excitations that can be captured are comparable to TDDFT. The pp-RPA for excitation calculation is further applied to challenging diradical problems and is used to unveil the nature of the ground and electronic excited states of higher acenes. The pp-RPA and the corresponding Tamm-Dancoff approximation (pp-TDA) are also applied to conical intersections, an important concept in nonadiabatic dynamics. Their good description of the double-cone feature of conical intersections is in sharp contrast to the failure of TDDFT. All in all, the pairing matrix fluctuation opens up new channel of thinking for quantum chemistry, and the pp-RPA is a promising method in describing ground and electronic excited states.

Design, Synthesis, and Photophysical Investigation of Porphyrin-containing Polymer-wrapped Single-walled Carbon Nanotubes

Significant advances in understanding the fundamental photophysical behavior of single-walled carbon nanotubes (SWNTs) have been made possible by the development of ionic, conjugated aryleneethynylene polymers that helically wrap SWNTs with well-defined morphology. My contribution to this work was the design and synthesis of porphyrin-containing polymers and the photophysical investigation of the corresponding polymer-wrapped SWNTs. For these new constructs, the polymer acts as more than just a solubilization scaffold; such assemblies can provide benchmark data for evaluating spectroscopic signatures of energy and charge transfer events and lay the groundwork for further, rational development of polymers with precisely tuned redox properties and electronic coupling with the underlying SWNT. The first design to incorporate a zinc porphyrin into the polymer backbone, PNES-PZn, suffered from severe aggregation in solution and was redesigned to produce the porphyrin-containing polymer S-PBN-PZn. This polymer was utilized to helically wrap chirality-enriched (6,5) SWNTs, which resulted in significant quenching of the porphyrin-based fluorescence. Time-resolved spectroscopy revealed a simultaneous rise and decay of the porphyrin radical cation and SWNT electron polaron spectroscopic signatures indicative of photoinduced electron transfer. A new polymer, S-PBN(b)-Ph2PZn3, was then synthesized which incorporated a meso-ethyne linked zinc porphyrin trimer. By changing the absorption profile and electrochemical redox potentials of the polymer, the photophysical behavior of the corresponding polymer-wrapped (6,5)-SWNTs was dramatically changed, and the polymer-wrapped SWNTs no longer showed evidence for photoinduced electron transfer.

Design, Fabrication, and Characterization of Carbon Nanotube Field Emission Devices for Advanced Applications

Carbon nanotubes (CNTs) have recently emerged as promising candidates for electron field emission (FE) cathodes in integrated FE devices. These nanostructured carbon materials possess exceptional properties and their synthesis can be thoroughly controlled. Their integration into advanced electronic devices, including not only FE cathodes, but sensors, energy storage devices, and circuit components, has seen rapid growth in recent years. The results of the studies presented here demonstrate that the CNT field emitter is an excellent candidate for next generation vacuum microelectronics and related electron emission devices in several advanced applications.

The work presented in this study addresses determining factors that currently confine the performance and application of CNT-FE devices. Characterization studies and improvements to the FE properties of CNTs, along with Micro-Electro-Mechanical Systems (MEMS) design and fabrication, were utilized in achieving these goals. Important performance limiting parameters, including emitter lifetime and failure from poor substrate adhesion, are examined. The compatibility and integration of CNT emitters with the governing MEMS substrate (i.e., polycrystalline silicon), and its impact on these performance limiting parameters, are reported. CNT growth mechanisms and kinetics were investigated and compared to silicon (100) to improve the design of CNT emitter integrated MEMS based electronic devices, specifically in vacuum microelectronic device (VMD) applications.

Improved growth allowed for design and development of novel cold-cathode FE devices utilizing CNT field emitters. A chemical ionization (CI) source based on a CNT-FE electron source was developed and evaluated in a commercial desktop mass spectrometer for explosives trace detection. This work demonstrated the first reported use of a CNT-based ion source capable of collecting CI mass spectra. The CNT-FE source demonstrated low power requirements, pulsing capabilities, and average lifetimes of over 320 hours when operated in constant emission mode under elevated pressures, without sacrificing performance. Additionally, a novel packaged ion source for miniature mass spectrometer applications using CNT emitters, a MEMS based Nier-type geometry, and a Low Temperature Cofired Ceramic (LTCC) 3D scaffold with integrated ion optics were developed and characterized. While previous research has shown other devices capable of collecting ion currents on chip, this LTCC packaged MEMS micro-ion source demonstrated improvements in energy and angular dispersion as well as the ability to direct the ions out of the packaged source and towards a mass analyzer. Simulations and experimental design, fabrication, and characterization were used to make these improvements.

Finally, novel CNT-FE devices were developed to investigate their potential to perform as active circuit elements in VMD circuits. Difficulty integrating devices at micron-scales has hindered the use of vacuum electronic devices in integrated circuits, despite the unique advantages they offer in select applications. Using a combination of particle trajectory simulation and experimental characterization, device performance in an integrated platform was investigated. Solutions to the difficulties in operating multiple devices in close proximity and enhancing electron transmission (i.e., reducing grid loss) are explored in detail. A systematic and iterative process was used to develop isolation structures that reduced crosstalk between neighboring devices from 15% on average, to nearly zero. Innovative geometries and a new operational mode reduced grid loss by nearly threefold, thereby improving transmission of the emitted cathode current to the anode from 25% in initial designs to 70% on average. These performance enhancements are important enablers for larger scale integration and for the realization of complex vacuum microelectronic circuits.

Nowhere Landscape, for Clarinets, Trombones, Percussion, Violins, and Electronics and “The Map and the Territory: Documenting David Dunn’s Sky Drift”

1. nowhere landscape, for clarinets, trombones, percussion, violins, and electronics

nowhere landscape is an eighty-minute work for nine performers, composed of acoustic and electronic sounds. Its fifteen movements invoke a variety of listening strategies, using slow change, stasis, layering, coincidence, and silence to draw attention to the sonic effects of the environment—inside the concert hall as well as the world outside of it. The work incorporates a unique stage set-up: the audience sits in close proximity to the instruments, facing in one of four different directions, while the musicians play from a number of constantly-shifting locations, including in front of, next to, and behind the audience.

Much of nowhere landscape’s material is derived from a collection of field recordings

made by the composer during a road trip from Springfield, MA to Douglas, WY along US- 20, a cross-country route made effectively obsolete by the completion of I-90 in the mid- 20th century. In an homage to artist Ed Ruscha’s 1963 book Twentysix Gasoline Stations, the composer made twenty-six recordings at gas stations along US-20. Many of the movements of nowhere landscape examine the musical potential of these captured soundscapes: familiar and anonymous, yet filled with poignancy and poetic possibility.

2. “The Map and the Territory: Documenting David Dunn’s Sky Drift”

In 1977, David Dunn recruited twenty-six musicians to play his work Sky Drift in the

Anza-Borrego Desert in Southern California. This outdoor performance was documented with photos and recorded with four stationary microphones to tape. A year later, Dunn presented the work in New York City as a “performance/documentation,” playing back the audio recording and projecting slides. In this paper I examine the consequences of this kind of act: what does it mean for a recording of an outdoor work to be shared at an indoor concert event? Can such a complex and interactive experience be successfully flattened into some kind of re-playable documentation? What can a recording capture and what must it exclude?

This paper engages with these questions as they relate to David Dunn’s Sky Drift and to similar works by Karlheinz Stockhausen and John Luther Adams. These case-studies demonstrate different solutions to the difficulty of documenting outdoor performances. Because this music is often heard from a variety of equally-valid perspectives—and because any single microphone only captures sound from one of these perspectives—the physical set-up of these kind of pieces complicate what it means to even “hear the music” at all. To this end, I discuss issues around the “work itself” and “aura” as well as “transparency” and “liveness” in recorded sound, bringing in thoughts and ideas from Walter Benjamin, Howard Becker, Joshua Glasgow, and others. In addition, the artist Robert Irwin and the composer Barry Truax have written about the conceptual distinctions between “the work” and “not- the-work”; these distinctions are complicated by documentation and recording. Without the context, the being-there, the music is stripped of much of its ability to communicate meaning.

Application of Numerical Methods to Study Arrangement and Fracture of Lithium-Ion Microstructure

The focus of this work is to develop and employ numerical methods that provide characterization of granular microstructures, dynamic fragmentation of brittle materials, and dynamic fracture of three-dimensional bodies.

We first propose the fabric tensor formalism to describe the structure and evolution of lithium-ion electrode microstructure during the calendaring process. Fabric tensors are directional measures of particulate assemblies based on inter-particle connectivity, relating to the structural and transport properties of the electrode. Applying this technique to X-ray computed tomography of cathode microstructure, we show that fabric tensors capture the evolution of the inter-particle contact distribution and are therefore good measures for the internal state of and electronic transport within the electrode.

We then shift focus to the development and analysis of fracture models within finite element simulations. A difficult problem to characterize in the realm of fracture modeling is that of fragmentation, wherein brittle materials subjected to a uniform tensile loading break apart into a large number of smaller pieces. We explore the effect of numerical precision in the results of dynamic fragmentation simulations using the cohesive element approach on a one-dimensional domain. By introducing random and non-random field variations, we discern that round-off error plays a significant role in establishing a mesh-convergent solution for uniform fragmentation problems. Further, by using differing magnitudes of randomized material properties and mesh discretizations, we find that employing randomness can improve convergence behavior and provide a computational savings.

The Thick Level-Set model is implemented to describe brittle media undergoing dynamic fragmentation as an alternative to the cohesive element approach. This non-local damage model features a level-set function that defines the extent and severity of degradation and uses a length scale to limit the damage gradient. In terms of energy dissipated by fracture and mean fragment size, we find that the proposed model reproduces the rate-dependent observations of analytical approaches, cohesive element simulations, and experimental studies.

Lastly, the Thick Level-Set model is implemented in three dimensions to describe the dynamic failure of brittle media, such as the active material particles in the battery cathode during manufacturing. The proposed model matches expected behavior from physical experiments, analytical approaches, and numerical models, and mesh convergence is established. We find that the use of an asymmetrical damage model to represent tensile damage is important to producing the expected results for brittle fracture problems.

The impact of this work is that designers of lithium-ion battery components can employ the numerical methods presented herein to analyze the evolving electrode microstructure during manufacturing, operational, and extraordinary loadings. This allows for enhanced designs and manufacturing methods that advance the state of battery technology. Further, these numerical tools have applicability in a broad range of fields, from geotechnical analysis to ice-sheet modeling to armor design to hydraulic fracturing.