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Towards first-principles biomimetic catalyst design

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Proof-of-principle calculations demonstrating the power of large-scale DFT methods, performed in TCM and other groups, are showing their relevance in studying systems of genuine biological interest. A benchmark study on a large portion of the enzyme chorismate mutase (CM), using linear-scaling density functional theory (DFT), will be discussed. Combined quantum mechanics/molecular mechanics (QM/MM) methods, where only the substrate and a few residues are treated quantum mechanically have become important within computational enzymology. A recent QM/MM study (Org. Biomol. Chem., 9, 157, (2011)) identified reaction pathways for the chorismate to prephenate rearrangement in solution and catalysed by CM. However, recent advances in linear-scaling DFT now allow the accurate prediction of transition state geometries and energetics whilst treating systems, comprising thousands of atoms, fully quantum mechanically. Such an approach allows a comparison with QM/MM approaches, using methods free from inaccuracies due to force field parameterisation and coupling between QM and MM regions. The DFT code ONETEP uniquely combines near-complete basis set accuracy with a computational cost that scales linearly with atom number, allowing an accurate QM description of the enzyme. Large-scale DFT calculations on structures from the CM pathways described above have been performed to address convergence of energies of activation and reaction with the number of protein atoms surrounding the active site. The calculations demonstrate the need for a DFT treatment in order to accurately determine interaction energies between substrate and enzyme, including the strain induced in the enzyme. Further understanding of enzymatic principles from an atomistic perspective will allow improved de novo computational enzyme design, enabling biomimetic design principles to be drawn from biological catalysts, utilising their properties to advance industrial catalytic processes.

This talk is part of the Electronic Structure Discussion Group series.

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