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This work establishes linear-scaling density-functional theory (DFT) as a powerful tool for understanding enzyme catalysis, one that can complement quantum mechanics/molecular mechanics (QM/MM) and molecular dynamics simulations. The thesis reviews benchmark studies demonstrating techniques capable of simulating entire enzymes at the ab initio quantum-mechanical level of accuracy. DFT has transformed the physical sciences by allowing researchers to perform parameter-free quantum-mechanical calculations to predict a broad range of physical and chemical properties of materials. In principle, similar methods could be applied to biological problems. However, even the simplest biological systems contain many thousands of atoms and are characterized by extremely complex configuration spaces associated with a vast number of degrees of freedom. The development of linear-scaling density-functional codes makes biological molecules accessible to quantum-mechanical calculation, but has yet to resolve the complexity of the phase space. Furthermore, these calculations on systems containing up to 2,000 atoms can capture contributions to the energy that are not accounted for in QM/MM methods (for which the Nobel prize in Chemistry was awarded in 2013) and the results presented here reveal profound shortcomings in said methods.
List of contents
Introduction.- Proteins, Enzymes and Biological Catalysis.- Computational Techniques.- Validation Studies.- Explaining the Closure of CHOMO-LUMO Gaps in Biomolecular Systems.- A Density-Functional Perspective on the Chorismate Mutase Enzyme.- Concluding Remarks.
About the author
Greg Lever obtained a first class M.Sc in Theoretical Physics from University College London (UCL) followed by a Ph.D. in Computational Enzymology at the Cavendish Laborator, University of Cambridge. He is now Postdoctoral Associate at the Massachusetts Institute of Technology (MIT) in the Department of Chemical Engineering.
Summary
This work establishes linear-scaling density-functional theory (DFT) as a powerful tool for understanding enzyme catalysis, one that can complement quantum mechanics/molecular mechanics (QM/MM) and molecular dynamics simulations. The thesis reviews benchmark studies demonstrating techniques capable of simulating entire enzymes at the ab initio quantum-mechanical level of accuracy. DFT has transformed the physical sciences by allowing researchers to perform parameter-free quantum-mechanical calculations to predict a broad range of physical and chemical properties of materials. In principle, similar methods could be applied to biological problems. However, even the simplest biological systems contain many thousands of atoms and are characterized by extremely complex configuration spaces associated with a vast number of degrees of freedom. The development of linear-scaling density-functional codes makes biological molecules accessible to quantum-mechanical calculation, but has yet to resolve the complexity of the phase space. Furthermore, these calculations on systems containing up to 2,000 atoms can capture contributions to the energy that are not accounted for in QM/MM methods (for which the Nobel prize in Chemistry was awarded in 2013) and the results presented here reveal profound shortcomings in said methods.
Additional text
“The dissertation is beautifully written in clear, precise language. It reads, in fact, almost as a textbook, providing in successive chapters the history, theory, and computational methods as background, then proceeding to discussing a validation computation followed by a detailed analysis of the importance of analyzing boundary conditions, then concluding with an analysis based on total use of DFT, and final thoughts. Anyone interested in this area can learn a great deal from this work.” (G. R. Mayforth, Computing Reviews, April, 2016)
Report
"The dissertation is beautifully written in clear, precise language. It reads, in fact, almost as a textbook, providing in successive chapters the history, theory, and computational methods as background, then proceeding to discussing a validation computation followed by a detailed analysis of the importance of analyzing boundary conditions, then concluding with an analysis based on total use of DFT, and final thoughts. Anyone interested in this area can learn a great deal from this work." (G. R. Mayforth, Computing Reviews, April, 2016)
