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
Molecular structure and function of the glycine receptor. This proposal will employ a cutting edge approach to reveal fundamental new insights into the ways that ligand-gated ion channels, and proteins in general, work. The new knowledge and technology developed here will broaden and strengthen Australia's research expertise across a number of basic scientific disciplines. The results will also have relevance to human health. Glycine receptors have an essential role in brain function and are ....Molecular structure and function of the glycine receptor. This proposal will employ a cutting edge approach to reveal fundamental new insights into the ways that ligand-gated ion channels, and proteins in general, work. The new knowledge and technology developed here will broaden and strengthen Australia's research expertise across a number of basic scientific disciplines. The results will also have relevance to human health. Glycine receptors have an essential role in brain function and are targets for anaesthetics and drugs of abuse. GlyRs are also important in modulating pain sensation by the brain. New insights into how natural agonists and drugs affect ion channel structure and function may lead to novel therapeutic opportunities and improved drug structure predictions.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
Complexity in a mesoscopic model of brain dynamics. Research into how the brain work remains at the frontier of human knowledge. We possess only the vaguest idea how the brain is able to generate memories, perceptions and behaviour. This research proposal concerns new approaches aimed at bridging this gap in our understanding by developing and studying detailed theories of the brain's electrical activity. The outcomes of this work will not only suggest improved diagnostic methods and treatments ....Complexity in a mesoscopic model of brain dynamics. Research into how the brain work remains at the frontier of human knowledge. We possess only the vaguest idea how the brain is able to generate memories, perceptions and behaviour. This research proposal concerns new approaches aimed at bridging this gap in our understanding by developing and studying detailed theories of the brain's electrical activity. The outcomes of this work will not only suggest improved diagnostic methods and treatments but contribute vital knowledge about how to control and predict the behaviour of complex systems.Read moreRead less
Mechanism of glutamate transport from experimental and simulation studies. Glutamate transporters play key roles in shaping the electrical signaling in the brain. Under conditions of stress or after a stroke, glutamate transporter function is impaired, which can lead to excessive levels of glutamate, cell death and impaired brain function. The project will help to decipher the operation of glutamate transporters at a molecular level and provide greater understanding of how glutamate levels are c ....Mechanism of glutamate transport from experimental and simulation studies. Glutamate transporters play key roles in shaping the electrical signaling in the brain. Under conditions of stress or after a stroke, glutamate transporter function is impaired, which can lead to excessive levels of glutamate, cell death and impaired brain function. The project will help to decipher the operation of glutamate transporters at a molecular level and provide greater understanding of how glutamate levels are controlled, which is vital for developing better treatments for neurological disorders such as stroke. The project will also provide research training in experimental/computational molecular biology, which is a rapidly growing field underpinning the biotechnological and pharmaceutical industries. Read moreRead less
Hierarchical modeling of protein interactions. Protein interactions play a central role in function and structural organization of cells. Their elucidation is essential for a better understanding of many cellular processes from signal transduction to enzyme inhibition. The aim of this project is to utilize the unprecedented powers of current supercomputers in developing a hierarchical model of protein interactions. The method combines Brownian dynamics at large distances and long time scales ....Hierarchical modeling of protein interactions. Protein interactions play a central role in function and structural organization of cells. Their elucidation is essential for a better understanding of many cellular processes from signal transduction to enzyme inhibition. The aim of this project is to utilize the unprecedented powers of current supercomputers in developing a hierarchical model of protein interactions. The method combines Brownian dynamics at large distances and long time scales with molecular dynamics at small distances and shorter times. Applications to both membrane proteins (blocking of ion channels by toxins and drugs) and globular proteins (ligand binding to receptors and protein association) will be considered.Read moreRead less
Activation mechanisms of Cys-loop ion channel receptors. This proposal will employ a cutting edge approach to reveal fundamental new insights into the ways that proteins work. The information and technology developed here will broaden and strengthen Australia's research expertise across a number of basic scientific disciplines. The results will also have relevance to human health. Cys-loop ligand-gated receptors have an essential role in brain function and are targets for many therapies and drug ....Activation mechanisms of Cys-loop ion channel receptors. This proposal will employ a cutting edge approach to reveal fundamental new insights into the ways that proteins work. The information and technology developed here will broaden and strengthen Australia's research expertise across a number of basic scientific disciplines. The results will also have relevance to human health. Cys-loop ligand-gated receptors have an essential role in brain function and are targets for many therapies and drugs of abuse. New insights into how biological ligands and drugs affect ion channel structure and function may lead to novel therapeutic opportunities and improved drug structure predictions.Read moreRead less
Verification of a theoretical model of the dynamical genesis of brain electrical activity. The physiological basis for the rhythmic scalp electrical activity known as the alpha rhythm has remained elusive despite being first recorded over eighty years ago. However, one of the applicants (DTJL) has developed a novel theory of the electroencephalogram (EEG) that theoretically articulates the necessary physiological conditions required for the genesis of this activity that is subject to rigorous e ....Verification of a theoretical model of the dynamical genesis of brain electrical activity. The physiological basis for the rhythmic scalp electrical activity known as the alpha rhythm has remained elusive despite being first recorded over eighty years ago. However, one of the applicants (DTJL) has developed a novel theory of the electroencephalogram (EEG) that theoretically articulates the necessary physiological conditions required for the genesis of this activity that is subject to rigorous experimental test. Empirical verification of this theory will pave the way to elucidating the functional importance of large scale brain electrical activity in neural information processing as well as enabling the rational use of the EEG for drug design and diagnosis.Read moreRead less
Theoretical Studies on the KcsA Potassium Channel and the L-type Calcium Channel. All electrical activities in the brain are regulated by opening and closing of ion channels. Thus, understanding their mechanisms is a fundamental problem in biology. The project is aimed at developing a theoretical model of two important types of ion channels. Using a supercomputer, we will first deduce the shape of the microstructure formed by a protein wall. Then, using a computer simulation technique, we will c ....Theoretical Studies on the KcsA Potassium Channel and the L-type Calcium Channel. All electrical activities in the brain are regulated by opening and closing of ion channels. Thus, understanding their mechanisms is a fundamental problem in biology. The project is aimed at developing a theoretical model of two important types of ion channels. Using a supercomputer, we will first deduce the shape of the microstructure formed by a protein wall. Then, using a computer simulation technique, we will construct a set of physical models of biological ion channels, which will correctly replicate experimental observations. Such a theory will link the structure and function of an ion channel through the fundamental principles of physics.Read moreRead less