AbstractProteins 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|
|Supervisor||Jean Van Den Elsen (Supervisor), Alison Walker (Supervisor) & Susan Crennell (Supervisor)|