MODELING THE CONDENSED-PHASE BEHAVIOR OF Π-CONJUGATED POLYMERS

It is well established that the morphology and physical properties of an organic semiconducting (OSC) material regulate its electronic properties. However, structure-function relationships remain difficult to describe in polymer-based OSC, which are of particular interest due to their robust mechanical properties. If relationships among the molecular and bulk levels of structure can be found, they can aid in the design of improved materials. To explore and detail important structure-function relationships in polymer-based OSC, this work employs molecular dynamics (MD) simulations to study various π-conjugated polymers in different environments. Two independent investigations are discussed in this work. One investigation examines how the purposeful disruption of the π-conjugated backbone to increase the chain flexibility impacts the chain structure and packing in the condensed phase. This is done by adding a conjugation break spacer (CBS) unit of one to ten carbons in length into the monomer structure of diketopyrrolopyrrole-based polymers. It is found that trends in the folding and glass structure follow the increase and the parity (odd versus even) of the CBS length. The second investigation analyzes a variety of polymers and small molecule acceptor (SMA) blends to observe the effects of changing the shape of either component and the physical properties of the material, as well as the structure of the polymer chains. It is found that the conjugated core, the side chains, and the planarity or sphericity each influence the density and diffusion of the materials made

Homology Modeling and Molecular Docking of Antagonists to Class B G-Protein Coupled Receptor Pituitary Adenylate Cyclase Type 1 (PAC1R)

Recent studies have identified the Class B g-protein coupled receptor (GPCR) pituitary adenylate cyclase activating polypeptide type 1 (PAC1R) as a key component in physiological stress management. Over-activity of neurological stress response systems due to prolonged or extreme exposure to traumatic events has led researchers to investigate PAC1R inhibition as a possible treatment for anxiety disorders such as post-traumatic stress disorder (PTSD). In 2008, Beebe and coworkers identified two such small molecule hydrazide antagonists and a general pharmacaphore for PAC1R inhibition. However, a relative dearth of information about Class B GPCRs in general, and PAC1R in specific, has significantly hindered progress toward the development of small molecule antagonists of PAC1R. The recent crystallization of the homologically similar glucagon receptor (GCGR) by Siu and coworkers in 2013, also a Class B receptor, has provided an experimentally resolved template from which to base computationally derived models of PAC1R. Initially, this research was focused towards synthesizing small molecule antagonists for PAC1R which were to be biologically screened via a qualitative western blot assay followed by a radioisotope binding assay for those hydrazides exhibiting down-stream signaling inhibitory capabilities. However, the resolution of the GCGR crystal structure shifted research objectives towards developing a homology model of PAC1R and evaluating that computationally created model with Beebe\u27s known small molecule antagonists. Created using academic versions of on-line resources including UniProtKB, Swiss-Model and Maestro, a homology model for PAC1R is presented here. The model is validated and evaluated for the presence of conserved Class B GPCR residues and motifs, including expected disulfide bridges, a conserved tyrosine residue, a GWGxP motif, a conserved glutamic acid residue and the extension of the transmembrane helix 1 (TM1) into the extra-cellular domain. Having determined this virtual PAC1R an acceptable model, ligand docking studies of known antagonists to the receptor were undertaken using AutoDock Vina in conjunction with AutoDock Tools and PyMol. Computational docking results were evaluated via comparison of theoretical binding affinity results to Beebe\u27s experimental data. Based on hydrogen bonding capabilities, several residues possibly key to the ligand-receptor binding complex are identified and include ASN 240, TYR 241 and HIST 365. Although the docking software does not identify non-bonding interactions other than hydrogen-bonding, the roles of additional proposed binding pocket residues are discussed in terms of hydrophobic interactions, π-π interactions and halogen bonding. These residues include TYR 161, PHE 196, VAL 203, PHE 204, ILE 209, LEU 210, VAL 237, TRP 297, PHE 362 and LEU 386. Although theoretical in nature, this reported homology modeling and docking exercise details a proposed binding site that may potentially further the development of drugs designed for the treatment of PTSD

A Hybrid Ray-Racing and Radiosity Method for Calculating Radiation Transport and Illuminance Distribution in Spaces With Venetian Blinds

This paper presents a hybrid ray-tracing and radiosity method for processing luminous flux in spaces equipped with venetian blinds. The method considers both diffuse and specular characteristics of blinds and aims to establish a balance between computational speed and accuracy. Specular components are treated using ray-tracing techniques using a shining factor for the blinds to split between directly and diffusely reflected components. The direct components are traced inside the blind cavity and inside the room while the direct-diffuse components inside the blind cavity are processed in a two-dimensional radiosity calculation until the final diffuse flux departing the cavity is determined. Diffuse-to-diffuse transmission is considered using a traditional radiosity method. Each room surface is divided into sub-surfaces and given an initial luminous exitance, after accounting for directly traced portions. Then a 3-D radiosity method is employed for the entire room to compute illuminance distributions on each subsurface and on the work plane. The developed model will help in the estimation of daylight distributions in spaces with venetian blinds and potential lighting energy savings calculations if combined with electric lighting controls. It will also lead to development of new control algorithms for shading and lighting systems for perimeter spaces with controllable shading devices

Developing methods to construct ring pucker free energy hypersurfaces applied to the analysis of glycosidase enzyme catalytic mechanisms

Includes bibliographical references.Carbohydrates consist of one or more sub-units usually various 5- and 6-membered cycles (furanoses and pyranoses) which can twist, bend or flip into a variety of conformers that differ in strain - this is ring puckering. These puckers notably the strained puckering conformers are observed during enzymatically assisted bond formation or cleavage of the glycosidic bonds of carbohydrate substrates. In this thesis, the free energy of ring puckering is calculated by implementing the Hill-Reilly reduced coordinate pucker description into the sampling enhancing Free Energies from Adaptive Reaction Coordinate Forces (FEARCF) method. FEARCF non-Boltzmann simulations of prototypical sugars β-Dribose and β-D-glucose converged to yield free energy pucker surfaces and volumes when using several semi-empirical QM methods - AM1, PM3, PM3CARB-1 and SCC-DFTB. From this, the accessible puckering conformations and minimum free energy paths of puckering were reasoned An analysis of the furanose and pyranose free energy pucker surfaces and volumes compared with both Density Functional Theory RB3LYP/6-311++G** optimised structures and a Hartree-Fock free energy surface revealed that SCC-DFTB provides the best semi-empirical description of 5- and 6- membered carbohydrate ring deformation. This illustrates that necessary high energy ring conformations observed in enzymatic binding sites requires the enzyme to induce and preserve high energy conformations required for successful hydrolyses and synthesis of the glycosidic bond. To further test this hypothesis, a 5- and 6-membered cycle were studied within enzymatic environments. The polysaccharide cellulose contains β 1-4 linked glucose subunit and is degraded by cellulase, a glycosidase. Specifically, the retaining cellobiohydrolase I (CBHI) of Trichoderma Reesei which cleaves cellobiose units from crystalline cellulose.The free energy volumes of puckering for the glucose sub-unit (in the catalytic position of an 8 unit cellulosic fragment - cellooctaose) were calculated and explored in vacuum, water and in the active site of CBHI. It was observed that the binding pocket of enzymes limits the ring pucker and that the active site amino acids preferentially stabilise certain puckering conformations. For CBHI, the first part of the glycosidase reaction is the glycosylation step. This was driven to completion during SCC-DFTB QM/MD FEARCF calculations where GLU212, ASP214 and GLU217 and part of the substrate were treated quantum mechanically. The general hybrid orbital method was used to connect the QM and MM regions. The free energy barriers of glycosylation were computed and the puckering statistics during the conversion of cellooctaose to products were correlated with this. Guanosine, a 5-membered ribose derivative is phosphorylated by Purine Nucleoside Phosphorylase (PNP) in order to salvage the guanine base. The effect of the PNP protein environment on ring pucker was studied by using FEARCF SCC-DFTB QM/MD non Boltzmann free energy calculations to quantify the pucker change induced in guanosine when changing environment from vacuum, to water and to the protein. In vacuo, the E4 and E1 pucker conformers were observed as minima. Upon solvation, the puckering phase space became less restricted with the 3T4 and 2T3 pucker conformers as minima. In the PNP active site pucker became restricted with only the 4E conformer observed

Stellar intensity interferometry over kilometer baselines: Laboratory simulation of observations with the Cherenkov Telescope Array

A long-held astronomical vision is to realize diffraction-limited optical aperture synthesis over kilometer baselines. This will enable imaging of stellar surfaces and their environments, show their evolution over time, and reveal interactions of stellar winds and gas flows in binary star systems. An opportunity is now opening up with the large telescope arrays primarily erected for measuring Cherenkov light in air induced by gamma rays. With suitable software, such telescopes could be electronically connected and used also for intensity interferometry. With no optical connection between the telescopes, the error budget is set by the electronic time resolution of a few nanoseconds. Corresponding light-travel distances are on the order of one meter, making the method practically insensitive to atmospheric turbulence or optical imperfections, permitting both very long baselines and observing at short optical wavelengths. Theoretical modeling has shown how stellar surface images can be retrieved from such observations and here we report on experimental simulations. In an optical laboratory, artificial stars (single and double, round and elliptic) are observed by an array of telescopes. Using high-speed photon-counting solid-state detectors and real-time electronics, intensity fluctuations are cross correlated between up to a hundred baselines between pairs of telescopes, producing maps of the second-order spatial coherence across the interferometric Fourier-transform plane. These experiments serve to verify the concepts and to optimize the instrumentation and observing procedures for future observations with (in particular) CTA, the Cherenkov Telescope Array, aiming at order-of-magnitude improvements of the angular resolution in optical astronomy.Comment: 18 pages, 11 figures; Presented at SPIE conference on Astronomical Telescopes + Instrumentation in Montreal, Quebec, Canada, June 2014. To appear in SPIE Proc.9146, Optical and Infrared Interferometry IV (J.K.Rajagopal, M.J.Creech-Eakman, F.Malbet, eds.), 201

Computational Fluid Dynamics Benchmark Validation Experiment of Plenum-to-Plenum Flow Through Vertical Heated Parallel Channels

The next generation of nuclear power plants will have higher efficiency and improved safety, among other benefits; one attractive option is the high temperature gas reactor. An ability to predict the physics that occur within the reactor under normal conditions and accident scenarios is necessary before it receives regulatory licensing for use. The flow through a high temperature gas reactor involves complex interactions of heat transfer, fluids, and solids. One method for simulating complex fluid dynamics is called Computational Fluid Dynamics. These simulations have already been used to predict the complex fluid flows found in high temperature gas reactors. Predicting the reactor fluid flows, especially during accident scenarios, is paramount for decision making, safety, and regulatory licensing. Using simulations for these purposes requires confidence in the simulation results. One scientific process to establish confidence in Computational Fluid Dynamics results is called validation. This dissertation describes a validation experiment that was completed to improve confidence in simulations of thermal-fluid flows of mixing jets, similar to those found in high temperature gas reactors. Validation experiments are vital in the process of simulation validation. A new wind tunnel test section with parallel heated channels was built specifically for this validation experiment. The product of this dissertation is a well described system along with archived measurement inputs and outputs for the simulation validation process. A validation experiment for these physics is not currently available

Virtual image out-the-window display system study. Volume 2 - Appendix

Virtual image out-the-window display system imaging techniques and simulation devices - appendices containing background materia

Molecular Dynamics

While many good textbooks are available on Protein Structure, Molecular Simulations, Thermodynamics and Bioinformatics methods in general, there is no good introductory level book for the field of Structural Bioinformatics. This book aims to give an introduction into Structural Bioinformatics, which is where the previous topics meet to explore three dimensional protein structures through computational analysis. We provide an overview of existing computational techniques, to validate, simulate, predict and analyse protein structures. More importantly, it will aim to provide practical knowledge about how and when to use such techniques. We will consider proteins from three major vantage points: Protein structure quantification, Protein structure prediction, and Protein simulation & dynamics. We know that many proteins have functional motions, and in Chapter "Structure Determination" we already introduced the famous example of the allosteric cooperative binding of oxygen to the haem group in hemoglobin. However, experimentally, such motions are hard to observe. Here, we will introduce MD simulations to investigate the dynamic behaviour of proteins. In a simulation the forces and interactions between particles are used to numerically derive the resulting three-dimensional movement of these particles over a certain time-scale. We will also highlight some applications, and will see how simulation results may be interpreted.Comment: editorial responsability: Halima Mouhib, Sanne Abeln, K. Anton Feenstra. This chapter is part of the book "Introduction to Protein Structural Bioinformatics". The Preface arXiv:1801.09442 contains links to all the (published) chapters. The update adds available arxiv hyperlinks for the chapter

Discovery by Virtual Screening of Ethionamide Boosters for Tuberculosis Treatment

Tuberculosis remains the world’s deadliest communicable bacterial disease with an unacceptably high death rate. In 2013 an estimated 1.5 million people died as a direct result of TB, and nine million new cases were reported. Multi-drug resistant (MDR) and extensively drug-resistant (XDR) tuberculosis cases are on the rise and without novel approaches to combat their spread, tuberculosis will continue to claim the lives of millions worldwide. One such novel approach is to rejuvenate the use of the second-line antibiotic ethionamide. Ethionamide is a structural analogue of the first-line pro-drug isoniazid, which is used widely and to which there is growing resistance. Ethionamide was introduced in the 1960s and primarily used in cases of drug-resistant TB due to its severe adverse effects. This makes ethionamide an exploitable target for small-molecule booster drugs. Expression of the enzyme responsible for ethionamide activation, EthA, is regulated by a transcriptional repressor EthR which can be inhibited to improve ethionamide activation and so reduce ethionamide treatment doses and bring an old drug new life in the clinic. EthR inhibitors are currently in development; here, chemoinformatic pipelining and virtual screening in GOLD were used to identify hits with novel scaffolds for hit-to-lead efforts from an initial library of over six million drug-like molecules. Thermal shift assays were used to identify EthR-binding molecules and SPR was utilised to confirm and potentially quantify binding affinities. Herein are reported the co-crystal structures of several hit molecules, used to confirm and characterise the EthR-ligand complexes. Through the application of computational, biophysical and crystallographic methods, this thesis presents several novel scaffolds for development against EthR. These novel hits will be developed to expand our arsenal against the growing, global problem of drug-resistant TB

NASA patent abstracts bibliography: A continuing bibliography. Section 1: Abstracts (supplement 29)

Abstracts are provided for 115 patents and patent applications entered into the NASA scientific and technical information system during the period January 1986 through June 1986. Each entry consists of a citation, an abstract, and in most cases, a key illustration selected from the patent application