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Title: Energy landscapes and dynamics of model proteins
Author: Carr, J. M.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2005
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The ‘protein folding problem’ is widely studied, from both an experimental and a computational standpoint. The scale of the resources devoted to this area of research reflects the importance of improving our currently incomplete understanding of how a protein can fold to a well-defined structure under physiological conditions. In the work presented in this thesis, we relate the properties of a protein to its underlying potential energy surface. Using computational methods, we focus on the most important features of the surface: the local minima and the transition states that connect them. Low-energy minima are located using global optimization approaches. Paths through configuration space are characterized in terms of connected sequences of minima and the intervening transition states. The ensemble of such paths between two groups of minima is explored using the discrete path sampling approach. Equilibrium properties are then calculated within the harmonic superposition approximation, and statistical rate theory is used to provide rate constants for transitions between directly connected minima. The folded structures of four small helical proteins are predicted using global optimization algorithms, on the basis of the hypothesis that the folded state is the most favoured thermodynamically. The performance of an approach that incorporates non-sequence-specific information from protein structural databases is compared to that of an existing, unbiased scheme. We then employ the discrete path sampling method to investigate the folding or the villin headpiece subdomain: a 36-residue protein fragment whose behaviour is thought to be characteristic of full proteins. This system offers a significant challenge to existing schemes for exploring and visualizing potential energy surfaces. An improved algorithm for constructing connected paths between local minima is presented and applied. The folding time is calculated using a number of approaches, and the order of folding events is determined using kinetic Monte Carlo simulations.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available