Understanding and predicting small molecule binding to G protein-coupled receptors (GPCRs). The discovery of new treatments for serious diseases is a time consuming and expensive process. Our work involves developing and testing new computational modelling approaches with experimental validation for the understanding and prediction of how current and new drugs interact with their targets, and these methods can be extended for improved understanding of how other proteins work. Our approaches have ....Understanding and predicting small molecule binding to G protein-coupled receptors (GPCRs). The discovery of new treatments for serious diseases is a time consuming and expensive process. Our work involves developing and testing new computational modelling approaches with experimental validation for the understanding and prediction of how current and new drugs interact with their targets, and these methods can be extended for improved understanding of how other proteins work. Our approaches have the potential to increase the speed, reduce the cost and lead to the discovery of new treatments for serious crippling diseases such as anxiety, depression, diabetes, and obesity. 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
Colorectal cancer is a common malignancy in Australia and the mutation of one gene (Apc) is implicated in >80% of the cases. We aim to understand Apc biochemistry in normal and colon cancer cells by integrating mathematics with our experimental biology program. The main outcomes for this project will be a better understanding of the regulatory systems perturbed in colon cancer. We believe that the insights gained by our research will point the way to more effective treatments of colon cancer.
Why is the photosynthetic CO2-fixing enzyme, Rubisco, so inefficient? Dissection of the catalytic chemistry by computational simulation and experimental testing. Fixation of CO2 by the enzyme Rubisco during photosynthesis produces organic compounds which feed all life. Despite this critical role, Rubisco catalyses its reaction sluggishly and, worse, discriminates poorly between CO2 and O2, leading to useless products. Our combined expertise equips us to analyse Rubisco's mechanism using quantum- ....Why is the photosynthetic CO2-fixing enzyme, Rubisco, so inefficient? Dissection of the catalytic chemistry by computational simulation and experimental testing. Fixation of CO2 by the enzyme Rubisco during photosynthesis produces organic compounds which feed all life. Despite this critical role, Rubisco catalyses its reaction sluggishly and, worse, discriminates poorly between CO2 and O2, leading to useless products. Our combined expertise equips us to analyse Rubisco's mechanism using quantum-chemical methods and then test predictions experimentally. We will capitalise on our previous successful studies of Rubisco by addressing emergent issues which are the keys to understanding catalytic efficiency and CO2/O2 selectivity: the roles of a carbamylated lysine; the way CO2 addition is rendered irreversible; and the spin inversion inherent in O2 addition.Read moreRead less
From structures to systems: A hierachical approach to understanding sub-cellular components. This program will dramatically extend the range of biomolecular systems that can be modelled with near atomistic precision. It will provide a better understanding of the structure and function of proteins involved in the regulation of membrane fusion and fission as well as shedding light on the assembly of large-scale protein-protein and protein-membrane complexes in general. The work will help place Au ....From structures to systems: A hierachical approach to understanding sub-cellular components. This program will dramatically extend the range of biomolecular systems that can be modelled with near atomistic precision. It will provide a better understanding of the structure and function of proteins involved in the regulation of membrane fusion and fission as well as shedding light on the assembly of large-scale protein-protein and protein-membrane complexes in general. The work will help place Australia at the forefront of developing simulation techniques in biomolecular systems, which are widely used within the chemical and pharmaceutical industries for modelling processes ranging from protein-drug interactions to the phase behaviour of lipids and surfactants. Read moreRead less
Increasing the Efficiency of Biomolecular Simulations. This program will extend the range of biomolecular systems that can be modelled with near atomistic precision. It will provide a better understanding of the structure and function of proteins involved in the regulation of membrane fusion and fission as well as shedding light on the assembly of large-scale protein-protein and protein-membrane complexes in general. The work will help place Australia at the forefront of developing simulation t ....Increasing the Efficiency of Biomolecular Simulations. This program will extend the range of biomolecular systems that can be modelled with near atomistic precision. It will provide a better understanding of the structure and function of proteins involved in the regulation of membrane fusion and fission as well as shedding light on the assembly of large-scale protein-protein and protein-membrane complexes in general. The work will help place Australia at the forefront of developing simulation techniques in biomolecular systems, which are widely used within the chemical and pharmaceutical industries. It will also provide opportunities for the training and development of young Australian researchers with top European laboratories. Read moreRead less
3D Structure determination of biomacromolecular assemblies from sparse data. This project has direct impact on pharmaceutical research: Biomacromolecular interactions are key points for pharmaceutical intervention and detailed structural knowledge of dynamic protein interactions can significantly accelerate drug development. Australia has invested in expensive instrumentation that can be used with new laboratory methods to obtain information on delicately balanced biomacromolecular interactions, ....3D Structure determination of biomacromolecular assemblies from sparse data. This project has direct impact on pharmaceutical research: Biomacromolecular interactions are key points for pharmaceutical intervention and detailed structural knowledge of dynamic protein interactions can significantly accelerate drug development. Australia has invested in expensive instrumentation that can be used with new laboratory methods to obtain information on delicately balanced biomacromolecular interactions, and how they malfunction in disease. This project will provide a computational framework to increase the impact of this investment by integrating measurements from a range of novel technologies and developing understanding of changes in structure of large protein complexes in different functional states.Read moreRead less