Abstract
Proteins are found throughout nature as the building blocks of life, and as such have been an area of great scientific interest since their initial discovery. Varying in size from hundreds to tens of millions of atoms, the task of modelling their motions and functions to resolve their behaviour has been a difficult one since the first protein MD simulations conducted in the mid 1970s by Levitt and Warshel. More recent years have seen the rise of flexibility based modelling methods, making use of simplified Hookean potentials and low frequency normal mode analysis, that are capable of accessing the size and time scales too complex for a typical all-atom full force field approach.In this doctoral thesis, I present my work in developing the next level of protein flexibility based modelling, and the Protein Conformational Freedom and Flexible Exploration with Elastic modes (ProCoFFEE) geometrical engine. The first of two main studies presented addresses the impact of salt bridges in thermophilic enzymes, and as a result re-formulates the calculation of non-covalent interactions in protein structures for rigid cluster decomposition. The latter describes a novel method for capitalizing on the heuristic nature of ProCoFFEE in order to access native motion in proteins with optimal pH in the acidic regime, and confirms its validity through comparison of bovine lysosomal α-mannosidase and its neutral Golgi-apparatus counterpart.
| Date of Award | 20 Nov 2019 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Jean Van Den Elsen (Supervisor), Alison Walker (Supervisor) & Susan Crennell (Supervisor) |