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
Intermolecular interactions revisited-Flaws in the fabric and applications to lower-dimensional structures. This project aims to capitalise on recent developments, that have shown that previously accepted theories are deeply flawed, in various applications in fundamental physics and in unsolved problems in biology that involve electromagnetic fields. Interactions driven
by electromagnetic fluctuation forces, and real photon exchange, between molecules will be investigated. The project will inv ....Intermolecular interactions revisited-Flaws in the fabric and applications to lower-dimensional structures. This project aims to capitalise on recent developments, that have shown that previously accepted theories are deeply flawed, in various applications in fundamental physics and in unsolved problems in biology that involve electromagnetic fields. Interactions driven
by electromagnetic fluctuation forces, and real photon exchange, between molecules will be investigated. The project will investigate how dispersion interactions change in mesoscopic pores, in electrolytes, and at finite temperatures. Applications involve
catalysis, molecular formation, and quantum logic. The project also aims to develop a unified theory for energy and charge transfer, relevant for photosynthesis and the way biological molecules transfer information.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
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
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