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
Characterising and exploiting hydrogen tunnelling in environmentally and medically important enzymes. Theory and experiment will be used to study environmentally and medically important enzymes, and quantify the role that hydrogen tunnelling plays in their activity. The project will determine the basis of their remarkable ability to catalyse chemical reactions, and to engineer and design more efficient proteins and pharmaceuticals.
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
Three-dimensional structure determination of biomolecular assemblies from sparse data of different length scales. New computer algorithms will be combined with sparse experimental structure restraints, obtained with novel protein chemistry technologies, to generate accurate three-dimensional (3D) models of proteins and protein assemblies in solution and in the solid state. The new strategies will greatly increase the number of protein targets amenable to rational drug design.
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE110100085
Funder
Australian Research Council
Funding Amount
$450,000.00
Summary
Regional facility for macromolecular x-ray crystallography. This facility in the southern NSW/ACT region will allow research into structures of biological molecules. Research at the facility will contribute to advances in understanding of processes in living organisms, new drugs and new biotechnology with national and international significance.
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE120100181
Funder
Australian Research Council
Funding Amount
$650,000.00
Summary
Strengthening merit-based access and support at the new National Computing Infrastructure petascale supercomputing facility. World-leading high-performance computing is fundamental to Australia's international research success. This facility will provide access to the new National Computational Infrastructure facility by world-leading researchers from six research universities, and sustain ground-breaking work in an increasingly competitive environment.
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE110100078
Funder
Australian Research Council
Funding Amount
$500,000.00
Summary
Establishment of a comprehensive regional biophysical analysis facility. Interactions between molecules are needed for cells to function correctly. This facility will permit comprehensive molecular characterisation as well as research into the fundamentals of how molecules interact.