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Title: Computational methods for characterising disordered states of proteins
Author: Allison, J. R.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2007
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To obtain a complete understanding of the behaviour of proteins it is necessary to characterise all accessible conformations. This includes not only folded structures, but also the partially and fully unfolded states populated during folding and mis-folding. The existence of intrinsically disordered proteins (IDPs) adds a further category. The heterogeneous range of structures comprising disordered states (DS) presents a challenge for structure determination, making an ensemble description essential. Recent advances in techniques such as nuclear magnetic resonance (NMR) spectroscopy allow site-specific structural information to be obtained for DS. This thesis focuses on the development of computational methods for characterising DS of proteins. Firstly, a range of existing techniques of varying degrees of accuracy are tested. Producing structures that are sufficiently expanded proves a major difficulty, and even when this is overcome, the structures remain incorrect. Long-range distances derived from paramagnetic relaxation enhancement (PRE)-NMR are therefore incorporated into ensemble-restrained molecular dynamics (ERMD) simulations to modulate the accessible conformations. The initial tests are conducted using synthetic data so that the success of the simulations can be evaluated by comparing distributions as well as averages. The methodology is improved to account for the anomalous effects of restraining a highly non-linear average across a limited number of replicas and the inability of a single type of average to report on the underlying distribution. The conversion of experimental data into distance restraints is also refined. The resulting general method is applied using experimental data for three IDPs and the acid-denatured state of a NFP and new analysis methods are introduced. The use of ERMD allows the aggregation propensities of the proteins to be rationalised in terms of the nature of their residual structure.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available