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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Importance of conformational and electrostatic contributions in simulations of enzyme reaction mechanisms. The research will contribute to the development of biomolecular simulation in Australia by demonstrating its potential to complement experiment, and also promote the effective use of APAC (Australian national supercomputer facilities) resources by providing advanced programs and computational protocols for other researchers. It will assist the diffusion of computational biology technology i ....Importance of conformational and electrostatic contributions in simulations of enzyme reaction mechanisms. The research will contribute to the development of biomolecular simulation in Australia by demonstrating its potential to complement experiment, and also promote the effective use of APAC (Australian national supercomputer facilities) resources by providing advanced programs and computational protocols for other researchers. It will assist the diffusion of computational biology technology into industrial applications such as rational drug design and protein engineering, as, for example, in our associated Linkage project grant, and provide novel insights into protein engineering and other sorts of design, which transcend concepts currently used in biomimetic chemistry.Read moreRead less
Hydrogen Abstraction in Chemical, Biochemical and Polymerization Processes. Hydrogen-abstraction reactions are of vital importance in the chemical, biochemical and polymerization processes that occur in everyday life. The objective of the proposed research is to improve our understanding of such reactions. State-of-the-art quantum chemistry calculations will be used to examine a broad range of hydrogen-abstraction reactions, and to obtain accurate information about the factors that influence suc ....Hydrogen Abstraction in Chemical, Biochemical and Polymerization Processes. Hydrogen-abstraction reactions are of vital importance in the chemical, biochemical and polymerization processes that occur in everyday life. The objective of the proposed research is to improve our understanding of such reactions. State-of-the-art quantum chemistry calculations will be used to examine a broad range of hydrogen-abstraction reactions, and to obtain accurate information about the factors that influence such reactions. Building on this work, more detailed case studies will be performed in two important areas: the hydrogen-abstraction steps in biochemical reactions mediated by coenzyme B12, and chain-transfer processes in conventional and controlled free-radical polymerization.Read moreRead less
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
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0344441
Funder
Australian Research Council
Funding Amount
$390,000.00
Summary
New Generation Metalloenzyme Magnetic Circular Dichroism Spectrometer Systems. Funding is sought to enhance the existing collaborations between UQ, ANU, Sydney and other universities in the study of metal-centred molecules of biological interest through the construction of advanced magnetic circular dichroism (MCD) spectrometers. These facilities will be the best instruments of their kind, and will enable researchers at Australian institutions to enhance the quality of their research and remain ....New Generation Metalloenzyme Magnetic Circular Dichroism Spectrometer Systems. Funding is sought to enhance the existing collaborations between UQ, ANU, Sydney and other universities in the study of metal-centred molecules of biological interest through the construction of advanced magnetic circular dichroism (MCD) spectrometers. These facilities will be the best instruments of their kind, and will enable researchers at Australian institutions to enhance the quality of their research and remain internationally competitive through the application of modern MCD spectroscopic techniques to the study of metal-centred biomolecules. These facilities will drive a number of programs in the area of metalloenzyme and photosystem II research.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0237664
Funder
Australian Research Council
Funding Amount
$900,000.00
Summary
High Resolution Mass Spectrometer for (MS)n Chemical Characterisation. A Fourier transform ion cyclotron resonance ("FT-ICR") mass spectrometer equipped with electrospray ionisation (ESI) plus a "benchtop" matrix assisted laser desorption ionisation time of flight (MALDI-TOF) mass spectrometer are required to support the research of ca 28 research groups, including 44 postdoctoral fellows, and 138 honours and postgraduate students. By means of its high resolution and (MS)n capabilities, the FT- ....High Resolution Mass Spectrometer for (MS)n Chemical Characterisation. A Fourier transform ion cyclotron resonance ("FT-ICR") mass spectrometer equipped with electrospray ionisation (ESI) plus a "benchtop" matrix assisted laser desorption ionisation time of flight (MALDI-TOF) mass spectrometer are required to support the research of ca 28 research groups, including 44 postdoctoral fellows, and 138 honours and postgraduate students. By means of its high resolution and (MS)n capabilities, the FT-ICR-MS will provide key structural information on a wide range of synthetic and natural chemical substances, including sequence (e.g. peptides) and fragmentation patterns, while the MALDI-TOF instrument will be used primarily for high through-put proteomic analyses.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE100100236
Funder
Australian Research Council
Funding Amount
$180,000.00
Summary
Facilities for spectroscopy and diffraction at high pressures. The provision of infrastructure for the study of novel materials under high pressures will enhance Australia's capability in creating new materials and in creating new devices that meet needs in communication, environment and medicine applications. The new facility will enable researchers to understand the response of structures to extreme pressures and will exploit the unique capabilities of the synchrotron light.
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0989374
Funder
Australian Research Council
Funding Amount
$550,000.00
Summary
South Australian High-Resolution and Ion-Mobility Mass Spectrometry Facility. The analytical facility will enhance (i) fundamental research to understand the mechanisms of the reactions of charged species with neutral molecules, and (ii) the provision of structural information, including the precise atomic composition of any molecule, small or large. Research supported by this facility includes (a)nanotechnology, including supramolecular chemistry, (b) bioscience: cancer research, neurodegenera ....South Australian High-Resolution and Ion-Mobility Mass Spectrometry Facility. The analytical facility will enhance (i) fundamental research to understand the mechanisms of the reactions of charged species with neutral molecules, and (ii) the provision of structural information, including the precise atomic composition of any molecule, small or large. Research supported by this facility includes (a)nanotechnology, including supramolecular chemistry, (b) bioscience: cancer research, neurodegenerate diseases (e.g. Parkinson's disease) osteoarthritis, inflammation, cardiac diseases and synthetic approaches to anticancer and other drugs.Read moreRead less
Elucidating the Mode of Action of Nicotinic Receptor Ligands. Changes in brain function can cause human diseases such as epilepsy, schizophrenia and Alzheimer's disease. To develop new medicines to treat these conditions we need to study how drugs act in the brain. This project will use new methods of chemistry to make drugs, which will then be tested for biological activity at important brain receptors. This will tell us which compounds are most effective as potential drugs and also exactly whe ....Elucidating the Mode of Action of Nicotinic Receptor Ligands. Changes in brain function can cause human diseases such as epilepsy, schizophrenia and Alzheimer's disease. To develop new medicines to treat these conditions we need to study how drugs act in the brain. This project will use new methods of chemistry to make drugs, which will then be tested for biological activity at important brain receptors. This will tell us which compounds are most effective as potential drugs and also exactly where they act in the brain. Read moreRead less
Elucidating the Mode of Action of Nicotinic Receptor Ligands. Changes in brain function can cause human diseases such as epilepsy, schizophrenia and Alzheimer's disease. To develop new medicines to treat these conditions we need to study how drugs act in the brain. This project will use new methods of chemistry to make drugs, which will then be tested for biological activity at important brain receptors. This will tell us which compounds are most effective as potential drugs and also exactly whe ....Elucidating the Mode of Action of Nicotinic Receptor Ligands. Changes in brain function can cause human diseases such as epilepsy, schizophrenia and Alzheimer's disease. To develop new medicines to treat these conditions we need to study how drugs act in the brain. This project will use new methods of chemistry to make drugs, which will then be tested for biological activity at important brain receptors. This will tell us which compounds are most effective as potential drugs and also exactly where they act in the brain. Read moreRead less