Berta, Dénes Gyula; (2022) Chemical and Enzymatic Catalysis from a Computational Perspective. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Herein I present the computational study of four (bio)chemical systems. I employed classical atomistic simulations as well as DFT calculations and hybrid QM/MM methods to gain structural insight and understanding of the catalytic function therein. This thesis covers two enzymes: the RNA helicase of SARS-CoV-2 and the human Ras GTPase. The presented helicase model demonstrates the importance of detailed modelling of holoproteins. Through extended classical simulations, we access the statistics and dynamics of substrate and allosteric pockets, ideal for building a specific drug development strategy. In contrast with the helicase, Ras GTPases have long been in the spotlight of research, yet they present a formidable challenge in cancer treatment. We elaborate the mechanistic possibilities and conclude that a base assisted pathway is preferred in the enzymatic environment. The model relies on the QM description of the crucial proton transfer steps, invisible to most experiments. The proposed mechanism is consistent with the reactivity of intrinsic and mutant Ras. Furthermore, a novel screening algorithm is developed to restore the lost activity in Ras mutants by mutations on its activating protein GAP. Although chemical catalysis is seldom as effective as enzymes evolved in million years, they constitute an important basis for chemical industries. Two sustainable and efficient catalytic systems are presented in this thesis. We provide an explanation to the catalytic effect of the supramolecular CB[7] on model Diels-Alder reactions, by analysing a number of factors the macrocycle influences. Most importantly, the substrate-solvent interaction is tailored to achieve the catalytic speedup. Finally, an organocatalytic Michael addition, with intriguing selectivity profile, is studied. We propose a detailed catalytic cycle based on DFT calculations to explain the product ratios. The application of the the accessed precursor briefly returns to the realm of biochemistry as we study peptidic foldamer structures using NMR experimental data.

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