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Strategies in the Computational Modelling of Biological Systems: Case Studies with Radical Enzymes

The research conducted in this thesis is based on the application of modern computational techniques to model biological systems. In particular, the focus of the thesis is oriented toward better understanding of structural and functional properties of the selected radical enzymes – pyruvate formate-lyase and (6-4) photolyase. The specific approaches that were used in the current thesis range from the calculation of spectroscopic parameters and pKa values to the construction of potential energy surfaces for chemical reactions and free energy changes associated with structural rearrangements. With such a multifaceted approach, it was possible to address a series of unresolved mechanistic issues relevant to the systems of interest. In particular, the use of a range of techniques enabled the investigation of the interconnectedness of processes taking place at different time and length scales. These techniques include very accurate ab initio methods, based on quantum mechanics, and coarser descriptions of the system relying on the classical mechanics, such as molecular dynamics and implicit solvation models. As molecular modelling continues to develop as an independent discipline, one can expect an ncreased number of similar applications, in which targeted techniques are combined to provide answers to questions of biological relevance.

computational modelling; radical enzyme; catalysis; QM/MM; molecular dynamics

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