Realistic models of permeation in ion channels. Ion channels are formed by proteins in cell membranes and provide pathways for fast and controlled flow of selected ions. This activity generates action potentials in nerves and muscles that forms the basis of all movement, sensation and thought processes. Recent determination of the crystal structure of channel proteins has enabled construction of models that can relate channel function to its structure--necessary for understanding their operati ....Realistic models of permeation in ion channels. Ion channels are formed by proteins in cell membranes and provide pathways for fast and controlled flow of selected ions. This activity generates action potentials in nerves and muscles that forms the basis of all movement, sensation and thought processes. Recent determination of the crystal structure of channel proteins has enabled construction of models that can relate channel function to its structure--necessary for understanding their operation and seeking cures for diseases caused by their malfunction. This project aims to develop accurate ion-protein-water interactions for permeation models based on stochastic and molecular dynamics simulations using both classical and quantum mechanical methods.Read moreRead less
Functional Dissection of the Bacterial Replisome. We now have the complete sequences of genes in humans and many other organisms, but we know much less about how the protein products of the genes communicate with each other to create and grow cells. Australia has recently invested heavily in state-of-the-art instruments that can be used to tackle these problems. This project will involve close interaction of four laboratories to use new instruments to determine how a large assembly of proteins i ....Functional Dissection of the Bacterial Replisome. We now have the complete sequences of genes in humans and many other organisms, but we know much less about how the protein products of the genes communicate with each other to create and grow cells. Australia has recently invested heavily in state-of-the-art instruments that can be used to tackle these problems. This project will involve close interaction of four laboratories to use new instruments to determine how a large assembly of proteins interact in a biological machine that makes DNA. This process occurs in similar ways in all organisms, and is essential for life. Understanding how DNA is made will help scientists to develop new antibacterial drugs, and learn how to make practical use of molecular machines that imitate biology.Read moreRead less
Electro-active and migratory peptides in lipid bilayers: NMR and biophysical studies. All living things are characterized by the separation of inner space from the surrounding medium by a self-assembling membrane. Selective entry and exit of water, ions and solutes is a defining feature of each type of cell. Some proteins sense the voltage difference across the cell membrane and open or close in response to voltage changes. Others, like bacterial toxins assemble in the membrane as pores, while o ....Electro-active and migratory peptides in lipid bilayers: NMR and biophysical studies. All living things are characterized by the separation of inner space from the surrounding medium by a self-assembling membrane. Selective entry and exit of water, ions and solutes is a defining feature of each type of cell. Some proteins sense the voltage difference across the cell membrane and open or close in response to voltage changes. Others, like bacterial toxins assemble in the membrane as pores, while other peptides migrate across the membrane piggy-backing their peptide cargo. The aim is to understand the molecular mechanisms in examples of these membrane-active peptides and proteins with a view to enabling rational intervention into their operation in situ in normal and disease states.Read moreRead less
Quantum mechanical and dynamical investigation of ion channels. Many genetic diseases result from mutations in the genes that transcribe the channel proteins. Ion channels are also primary targets for development of therapeutic drugs for many ailments. Development of proper simulation tools is essential for a molecular-level understanding of their operation, which will be very helpful in finding treatments for genetic diseases as well as new drugs that target ion channels. Another aim of the p ....Quantum mechanical and dynamical investigation of ion channels. Many genetic diseases result from mutations in the genes that transcribe the channel proteins. Ion channels are also primary targets for development of therapeutic drugs for many ailments. Development of proper simulation tools is essential for a molecular-level understanding of their operation, which will be very helpful in finding treatments for genetic diseases as well as new drugs that target ion channels. Another aim of the project is to provide research training in computational biology. Research in this area is rapidly growing elsewhere but it has been rather neglected in Australia, and there is a shortage of researchers with such skills at present.Read moreRead less
Mathematical measurement and modelling of neuronal degeneration. Currently about 150,000 Australian's suffer from cognitive impairment due to Alzheimer's disease or dementia and this number is expected to double over the next few decades. By combining newly developed mathematical methods in complex systems with sophisticated neural imaging we will develop new techniques to advance the diagnosis and treatment of cognitive decline in normal ageing and neurodegenerative disease.
This project will ....Mathematical measurement and modelling of neuronal degeneration. Currently about 150,000 Australian's suffer from cognitive impairment due to Alzheimer's disease or dementia and this number is expected to double over the next few decades. By combining newly developed mathematical methods in complex systems with sophisticated neural imaging we will develop new techniques to advance the diagnosis and treatment of cognitive decline in normal ageing and neurodegenerative disease.
This project will also maintain the collaborative link between researchers in Biomathematics at Mount Sinai School of Medicine, New York and researchers in Applied Mathematics at UNSW that enables training of Australian scientists in the vital area of mathematical bio-complexity.Read moreRead less
Mapping Protein Contacts and Conformational Changes in Macromolecular Assemblies. We now have a great deal of information about the structures of proteins that interact to do much of the chemistry that governs the lives of cells and organisms, but are just beginning to understand how proteins communicate with each other in the large, dynamic molecular machines that carry out many cellular functions. Australia has invested in expensive instrumentation that can be used in conjunction with new labo ....Mapping Protein Contacts and Conformational Changes in Macromolecular Assemblies. We now have a great deal of information about the structures of proteins that interact to do much of the chemistry that governs the lives of cells and organisms, but are just beginning to understand how proteins communicate with each other in the large, dynamic molecular machines that carry out many cellular functions. Australia has invested in expensive instrumentation that can be used in conjunction with new laboratory methods to develop better understanding of how these machines work, and how they malfunction in disease. This project will bring together four scientists with a unique combination of expertise and novel technologies to develop understanding of changes in structure of a large protein complex in different functional states.Read moreRead less
Cytorefractometry - a new technique for refractive index tomography of living cells. An ultrahigh-resolution bifocal optical coherence refractometry is proposed, and will result to micron-scale-resolution refractive index tomography of living cells, termed cytorefractometry. This technique represents an extension from bifocal optical coherence refractometry that has recently shown a remarkable promise for direct, several-frames-per-second, motion-artifact-free determination of refractive index ....Cytorefractometry - a new technique for refractive index tomography of living cells. An ultrahigh-resolution bifocal optical coherence refractometry is proposed, and will result to micron-scale-resolution refractive index tomography of living cells, termed cytorefractometry. This technique represents an extension from bifocal optical coherence refractometry that has recently shown a remarkable promise for direct, several-frames-per-second, motion-artifact-free determination of refractive index in turbid media, including biological tissue in vivo. We propose to apply our novel technique to study tissue calcification, a serious problem in cardiology, by making use of the refractive index contrast mechanism. Calcification of smooth muscle cells and aorta subdermal implant models will be studied aiming for prevention of calcification-associated pathologies.Read moreRead less
Microfluidic device for microbial separation and concentration. This project will enhance Australia's capabilities and presence in the rapidly expanding field of chemical and biological analysis systems on a chip. We will develop and build handheld devices for microbial concentration that will facilitate earlier and easier detection of potentially pathogenic organisms in critical situations such as epidemiological crises or forensics. The portability and ease of operation of our integrated micro ....Microfluidic device for microbial separation and concentration. This project will enhance Australia's capabilities and presence in the rapidly expanding field of chemical and biological analysis systems on a chip. We will develop and build handheld devices for microbial concentration that will facilitate earlier and easier detection of potentially pathogenic organisms in critical situations such as epidemiological crises or forensics. The portability and ease of operation of our integrated microfluidic devices and their increased resilience to blockages make them ideal for use in remote areas and non-laboratory settings. Application areas will include disease detection, microbial contamination in food industries and water quality monitoring.Read moreRead less
Characterisation of the CLIC1 chloride ion channel by a novel biophysical method: Site-Directed-Spin-Labeling Electron Paramagnetic Resonance Spectroscopy. Chloride ion channels are involved in diverse physiological processes and channel malfunction can lead to severe diseases. This project examines the structure and conformational changes of a member of the newly described chloride channel family (CLIC1) using an emerging biophysical technique. CLIC1 is unique due to its ability to transit be ....Characterisation of the CLIC1 chloride ion channel by a novel biophysical method: Site-Directed-Spin-Labeling Electron Paramagnetic Resonance Spectroscopy. Chloride ion channels are involved in diverse physiological processes and channel malfunction can lead to severe diseases. This project examines the structure and conformational changes of a member of the newly described chloride channel family (CLIC1) using an emerging biophysical technique. CLIC1 is unique due to its ability to transit between soluble and active membrane channel forms. Our novel approach to determine the channel structure represents a major advance in overcoming numerous difficulties associated with traditional atomic resolution structural-biology techniques. This proposal also opens up new experimental avenues to understand biological important events associated with ion channels, including channel gating.Read moreRead less
NMR studies of membrane proteins and peptides in novel amphiphilic mesophases. Membrane proteins are the next frontier in structural biology. Our goal is the structural and mechanistic characterization of the proteins and peptides from platypus venom and a cardiac potassium ion channel, HERG, that has a particular role in the suppression of cardiac arrhythmias. To do this we will refine and develop methods using amphiphilic mesophases and micelles and state-of-the-art NMR spectroscopy. Electrop ....NMR studies of membrane proteins and peptides in novel amphiphilic mesophases. Membrane proteins are the next frontier in structural biology. Our goal is the structural and mechanistic characterization of the proteins and peptides from platypus venom and a cardiac potassium ion channel, HERG, that has a particular role in the suppression of cardiac arrhythmias. To do this we will refine and develop methods using amphiphilic mesophases and micelles and state-of-the-art NMR spectroscopy. Electrophysiological analysis of ion channels and interactions with toxins will relate NMR structures to function. The NMR methodologies we develop will have broad applicability to membrane proteins in general.
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