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Genome-Wide Identification and 3D Modeling of Proteins involved in DNA Damage Recognition and Repair (Final Report)

Description: DNA Damage Recognition and Repair (DDR&R) proteins play a critical role in cellular responses to low-dose radiation and are associated with cancer. We have performed a systematic, genome-wide computational analysis of genomic data for human genes involved in the DDR&R process. The significant achievements of this project include: 1) Construction of the computational pipeline for searching DDR&R genes, building and validation of 3D models of proteins involved in DDR&R; 2) Functional and structural annotation of the 3D models and generation of comprehensive lists of suggested knock-out mutations; and the development of a method to predict the effects of mutations. Large scale testing of technology to identify novel small binding pockets in protein structures leading to new DDRR inhibitor strategies 3) Improvements of macromolecular docking technology (see the CAPRI 1-3 and 4-5 results) 4) Development of a new algorithm for improved analysis of high-density oligonucleotide arrays for gene expression profiling; 5) Construction and maintenance of the DNA Damage Recognition and Repair Database; 6) Producing 15 research papers (12 published and 3 in preparation).
Date: August 12, 2005
Creator: Abagyan, Ruben & An, Jianghong
Partner: UNT Libraries Government Documents Department

Biomolecular Simulation Using Amber and CHARMM

Description: This project supports the development of software using terascale computers to carry out molecular simulations of protein function and macromolecular interactions. We are building on the existing CHARMM and Amber simulation packages, adapting them in novel ways to massively parallel architectures and high-performance CPUs. Three principal avenues being pursued are: (1) Improvements in load-balancing and communication for large-scale particle-mesh Ewald (PME) simulations of solvated biomolecules. (2) Modern techniques for accelerating convergence of sampling of configuration space offer promise for further exploitation of massively parallel architectures. These methods include parallel tempering and ''lambda dynamics'' procedures that connect multiple, synchronized results from PME simulations like those described in part [1]. (3) The implementation of efficient and scalable algorithms that move towards lower-resolution models in ways that can be carefully calibrated against atomic-level solvated simulations.
Date: November 29, 2004
Creator: Case, David A. & Brooks, Charles L., III
Partner: UNT Libraries Government Documents Department

Genome-Wide Identification and 3D Modeling of Proteins involved in DNA Damage Recognition and Repair (Final Report)

Description: OAK-B135 DNA Damage Recognition and Repair (DDR and R) proteins play a critical role in cellular responses to low-dose radiation and are associated with cancer. the authors have performed a systematic, genome-wide computational analysis of genomic data for human genes involved in the DDR and R process. The significant achievements of this project include: (1) Construction of the computational pipeline for searching DDR and R genes, building and validation of 3D models of proteins involved in DDR and R; (2) Functional and structural annotation of the 3D models and generation of comprehensive lists of suggested knock-out mutations; (3) Important improvement of macromolecular docking technology and its application to predict the DNA-Protein complex conformation; (4) Development of a new algorithm for improved analysis of high-density oligonucleotide arrays for gene expression profiling; (5) Construction and maintenance of the DNA Damage Recognition and Repair Database; and (6) Producing 14 research papers (10 published and 4 in preparation).
Date: April 15, 2004
Creator: Ruben A. Abagyan, PhD
Partner: UNT Libraries Government Documents Department

Membrane Targeting of P-type ATPases in Plant Cells

Description: How membrane proteins are targeted to specific subcellular locations is a very complex and poorly understood area of research. Our long-term goal is to use P-type ATPases (ion pumps), in a model plant system Arabidopsis, as a paradigm to understand how members of a family of closely related membrane proteins can be targeted to different subcellular locations. The research is divided into two specific aims. The first aim is focused on determining the targeting destination of all 10 ACA-type calcium pumps (Arabidopsis Calcium ATPase) in Arabidopsis. ACAs represent a plant specific-subfamily of plasma membrane-type calcium pumps. In contrast to animals, the plant homologs have been found in multiple membrane systems, including the ER (ACA2), tonoplast (ACA4) and plasma membrane (ACA8). Their high degree of similarity provides a unique opportunity to use a comparative approach to delineate the membrane specific targeting information for each pump. One hypothesis to be tested is that an endomembrane located ACA can be re-directed to the plasma membrane by including targeting information from a plasma membrane isoform, ACA8. Our approach is to engineer domain swaps between pumps and monitor the targeting of chimeric proteins in plant cells using a Green Fluorescence Protein (GFP) as a tag. The second aim is to test the hypothesis that heterologous transporters can be engineered into plants and targeted to the plasma membrane by fusing them to a plasma membrane proton pump. As a test case we are evaluating the targeting properties of fusions made between a yeast sodium/proton exchanger (Sod2) and a proton pump (AHA2). This fusion may potentially lead to a new strategy for engineering salt resistant plants. Together these aims are designed to provide fundamental insights into the biogenesis and function of plant cell membrane systems.
Date: June 30, 2004
Creator: Jeffrey F. Harper, Ph.D.
Partner: UNT Libraries Government Documents Department

Heavy Metal Pumps in Plants

Description: The long term goal of the funded research is to understand how heavy metals are taken up from the soil and translocated throughout the plant. The potential application of this research is to create plants with better heavy metal uptake systems and thereby improve the ability of these plants to help clean up toxic metals from soils. A rate limiting step is using plant for bioremediation is the normally poor capacity of plants to concentrate toxic metals. Our interest in metal ion transport systems includes those for essential mineral nutrients such as molybdenum, copper, iron, manganese, as well as toxic metals such as cerium, mercury, cesium, cadmium, arsenic and selenium. Understanding the pathways by which toxic metals accumulate in plants will enable the engineering of plants to exclude toxic metals and create healthier food sources, or to extract toxic metals from the soil as a strategy to clean up polluted lands and water.
Date: October 1, 2000
Creator: Harper, J. F.
Partner: UNT Libraries Government Documents Department

Engineered Antibodies for Monitoring of Polynuclear Aromatic Hydrocarbons

Description: Polynuclear aromatic hydrocarbons (PAHs) are a large class of structurally similar pollutants. Rapid, inexpensive, and high-throughput methods to identify and monitor PAHs are needed in several DOE focus areas, including human and ecosystem health effects, risk and exposure assessment, decontamination and decommissioning, and remediation. DOE has sponsored and participated in several demonstration projects in which commercial immunoassay kits proved useful and cost-effective for detection of PAHs and other pollutants. The emerging generation of sensors and residue recovery methods will require panels of antibodies with relatively subtle differences in cross-reactivity. This project is based on the premise that genetic engineering should be much more successful than conventional polyclonal and monoclonal antibody methods for developing these antibody panels. One objective of this project has been to define the structural basis and mechanisms by which antibodies bind and cross-react with various PAHs. A second objective has been to use this information to produce recombinant antibodies with improved performance in analytical procedures that DOE can use. A third objective has been development of PAH residue recovery and cleanup methods that will be compatible with immunoassays, and make instrumental analysis faster, more accurate, and less expensive.
Date: March 6, 2000
Creator: Karu, Alexander E.; Roberts, Victoria A. & Li, Qing X.
Partner: UNT Libraries Government Documents Department

Engineered Antibodies for Monitoring of Polynuclear Aromatic Hydrocarbons

Description: The objective is to develop improved antibody-based methods for detection of multiple polynuclear aromatic hydrocarbons (PAHs), to fill several needs in DOE's remediation, regulatory monitoring, ecotoxicology, and human health effects missions. Present-generation immunochemical detection methods have already proven to be useful and cost-effective in DOE applications. The problem being addressed is that the unique properties of PAHs make it impractical to generate antibodies with the required diversity, specificity and selectivity, by the previous techniques. The scientific goals are to determine the mechanisms by which antibodies bind PAHs, use genetic engineering and computational chemistry techniques to construct improved antibodies, and to devise methods for making immunochemical and instrumental analysis more compatible. The potential relevance is that our results should provide a rational basis by which immunochemical and other molecular recognition systems for PAHs and other large classes of toxic pollutants such as PCBs could be produced and deployed with substantially less cost, labor, and development time.
Date: June 1, 1999
Creator: Karu, Alexander E.; Roberts, Victoria & Li, Qingxiao
Partner: UNT Libraries Government Documents Department