Mathematical Methods for Next Generation Sequencing. The emergence of a new generation of high throughput genomic sequencing technologies is providing unprecedented opportunities for biological research. Hidden within the huge amounts of data generated by this technology is information about the expression and regulation of genes, and the complex functional purpose of non-coding, so called 'junk', DNA. Development of mathematical and statistical tools is essential to interpreting these data. The ....Mathematical Methods for Next Generation Sequencing. The emergence of a new generation of high throughput genomic sequencing technologies is providing unprecedented opportunities for biological research. Hidden within the huge amounts of data generated by this technology is information about the expression and regulation of genes, and the complex functional purpose of non-coding, so called 'junk', DNA. Development of mathematical and statistical tools is essential to interpreting these data. The proposed research will enhance Australia's reputation for developing novel quantitative techniques at the cutting edge of modern biology. The proposed project has a broad range of potential applications in biotechnology, particularly in the medical and agricultural industries.Read moreRead less
Enabling Technologies for Structural Genomics. New technologies will be developed to save time, money and effort in rapid preparation of protein samples for structural genomics. Systems will be devised for preparing sufficient isotope-labelled proteins for nuclear magnetic resonance spectroscopy without using living organisms, for efficiently identifying points at which proteins can be broken into smaller fragments with the right properties, and for joining the ends of proteins and peptides toge ....Enabling Technologies for Structural Genomics. New technologies will be developed to save time, money and effort in rapid preparation of protein samples for structural genomics. Systems will be devised for preparing sufficient isotope-labelled proteins for nuclear magnetic resonance spectroscopy without using living organisms, for efficiently identifying points at which proteins can be broken into smaller fragments with the right properties, and for joining the ends of proteins and peptides together to make them much more stable. This combination of technologies are widely applicable to current problems in protein chemistry, molecular biology, functional genomics and the medical sciences.Read moreRead less
TOWARDS A COMPLETE DESCRIPTION OF HOW ENZYMES WORK: development of simulation methods and protocols, blind test predictions, and experimental validation. Enzymes catalyze quite fantastic chemistry under mild physiological conditions. Many special chemical concepts (such as "transition-state stabilization" and "entropy-enthalpy compensation") proposed to explain these powers are unnecessary. Uniquely for a catalyst, these powers are integral to the structure, properties and dynamics of the protei ....TOWARDS A COMPLETE DESCRIPTION OF HOW ENZYMES WORK: development of simulation methods and protocols, blind test predictions, and experimental validation. Enzymes catalyze quite fantastic chemistry under mild physiological conditions. Many special chemical concepts (such as "transition-state stabilization" and "entropy-enthalpy compensation") proposed to explain these powers are unnecessary. Uniquely for a catalyst, these powers are integral to the structure, properties and dynamics of the protein, as constrained and selected by evolution. The question is how do they work? Answering this requires energetic and thermodynamic analysis beyond current experimental techniques, but accessible by computer simulation. We aim to develop a robust toolkit of simulation methods and protocols, blind test them by predicting the mechanism of a new enzyme, with followup experimental validation.
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Protein degradation in mammals. One mechanism by which the regulation of protein turnover occurs is the balance between the activity of enzymes responsible for the ubiquitination and deubiquitination of target proteins. The majority of targets of this second family of enzymes are unknown. This project proposes a method for the identification of the targets of two specific mammalian deubiquitinating enzymes in order to understand their function and to begin to explore this new research field. ....Protein degradation in mammals. One mechanism by which the regulation of protein turnover occurs is the balance between the activity of enzymes responsible for the ubiquitination and deubiquitination of target proteins. The majority of targets of this second family of enzymes are unknown. This project proposes a method for the identification of the targets of two specific mammalian deubiquitinating enzymes in order to understand their function and to begin to explore this new research field. Knowledge about this new aspect of protein degradation could provide a powerful tool to test the effect of the stabilisation or removal of specific proteins in the cell and also to develop new technologies in protein production.Read moreRead less
Kingdom switching microbial pathogens: the bioinformatics of mutation in the genomes of viruses and bacteria affecting crops, livestock and people. Some organisms that cause infectious diseases have moved between plants and vertebrates, either recently or repeatedly over evolutionary time. Switching between plants and vertebrates strongly influences the way these microbes mutate and evolve. We will search the genomic sequence databases for information about how the choice of host influences muta ....Kingdom switching microbial pathogens: the bioinformatics of mutation in the genomes of viruses and bacteria affecting crops, livestock and people. Some organisms that cause infectious diseases have moved between plants and vertebrates, either recently or repeatedly over evolutionary time. Switching between plants and vertebrates strongly influences the way these microbes mutate and evolve. We will search the genomic sequence databases for information about how the choice of host influences mutations in viral and bacterial genomes and model the evolutionary processes involved. This project will advance our understanding of the fine structure of microbial genomes and the importance of selection pressures on genes. It will lead to better disease management strategies for humans, and for domestic crops and livestock.Read moreRead less
Theoretical and experimental studies on magnetoelectroelastic bone remodelling process. The project combines biotechnology and material science which will have national economic, social and environment impact. It can benefit industry by providing knowledge that help scientists understand remodeling under coupled fields and is used to develop bone replacement. By better understanding remodeling due to multi-field loading, we can assist scientists in aeronautical industry in developing countermeas ....Theoretical and experimental studies on magnetoelectroelastic bone remodelling process. The project combines biotechnology and material science which will have national economic, social and environment impact. It can benefit industry by providing knowledge that help scientists understand remodeling under coupled fields and is used to develop bone replacement. By better understanding remodeling due to multi-field loading, we can assist scientists in aeronautical industry in developing countermeasures that reduce or eliminate bone loss resulting from long-duration space flight. It can provide knowledge that can be used to explore underlying mechanisms controlling bone remodeling and self-repair in gaining insight into debilitating diseases such as osteoporosis, to develop high-performance prosthetics for medical injury healing.Read moreRead less
New Methods for Structural Biology in Solution. This project aims to expand the range of applications of nuclear magnetic resonance (NMR) spectroscopy in pharmaceutical research, where NMR spectroscopy is already used routinely for the identification of chemical compounds that bind to protein targets. The techniques developed aim at providing rapid and broadly applicable tools for 3D structure determinations of chemical compounds bound to their protein target, identification of protein-protein i ....New Methods for Structural Biology in Solution. This project aims to expand the range of applications of nuclear magnetic resonance (NMR) spectroscopy in pharmaceutical research, where NMR spectroscopy is already used routinely for the identification of chemical compounds that bind to protein targets. The techniques developed aim at providing rapid and broadly applicable tools for 3D structure determinations of chemical compounds bound to their protein target, identification of protein-protein interaction sites and characterization of protein motions. The limits of NMR spectroscopy will be pushed to analyse systems of significantly increased molecular weights. The project includes applications to drug targets such as the dengue virus NS2B/NS3 protease.Read moreRead less
Fluorine-labelled proteins for NMR spectroscopy. The technique developed in this project has direct impact on pharmaceutical research: NMR spectroscopy is used routinely to identify chemical compounds that bind to protein targets. This project includes the development of novel assignment techniques of 19F-labelled proteins, so that 19F-NMR can be used to detect specific binding interactions. One of the methods proposed here is designed to reveal structural information about the binding mode in s ....Fluorine-labelled proteins for NMR spectroscopy. The technique developed in this project has direct impact on pharmaceutical research: NMR spectroscopy is used routinely to identify chemical compounds that bind to protein targets. This project includes the development of novel assignment techniques of 19F-labelled proteins, so that 19F-NMR can be used to detect specific binding interactions. One of the methods proposed here is designed to reveal structural information about the binding mode in solution with atomic detail. This knowledge can significantly accelerate drug development. It is otherwise only available from crystal structures that can not always be determined.Read moreRead less
New Methods for Structural Biology in Solution. New technologies will be developed that are sufficiently rapid and inexpensive to compete with and replace the mutagenesis experiments that biologists usually perform to identify and characterize the functionally important parts of a protein. Nuclear magnetic resonance (NMR) spectroscopy techniques in combination with various selective labelling schemes will be developed with the goal of identification and structural characterization of protein-lig ....New Methods for Structural Biology in Solution. New technologies will be developed that are sufficiently rapid and inexpensive to compete with and replace the mutagenesis experiments that biologists usually perform to identify and characterize the functionally important parts of a protein. Nuclear magnetic resonance (NMR) spectroscopy techniques in combination with various selective labelling schemes will be developed with the goal of identification and structural characterization of protein-ligand interactions at increased rates and enhanced accuracy. In addition, the three-dimensional structures of proteins and protein domains of biologically important functions and unknown fold will be determined by NMR. The project aims at techniques of direct impact in pharmaceutical industry.Read moreRead less
Evolvability and the Evolution of Complexity. Anyone engaging in a moment's reflection on the striking richness, diversity, and complexity of the biological world is faced with the question: how did it get here? Though natural selection is central to answering this question, important new work has identified various conditions that make some lineages of organisms "evolvable": capable of changing in ways that radically expand the range of further possible changes. This project will clarify and in ....Evolvability and the Evolution of Complexity. Anyone engaging in a moment's reflection on the striking richness, diversity, and complexity of the biological world is faced with the question: how did it get here? Though natural selection is central to answering this question, important new work has identified various conditions that make some lineages of organisms "evolvable": capable of changing in ways that radically expand the range of further possible changes. This project will clarify and integrate these various conditions using empirical examples and simple models. The resulting work from this project will provide a clearer general understanding of what biological complexity is, and how science has compelling candidates for understanding how it evolves.Read moreRead less