Molecular simulations of conformational transitions in biomolecules using a novel computational tool

De Marco, Giuseppe (2011) Molecular simulations of conformational transitions in biomolecules using a novel computational tool. Doctoral thesis (DPhil), University of Sussex.

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The function of biological macromolecules is inherently linked to their complex
conformational behaviour. As a consequence, the corresponding potential energy
landscape encompasses multiple minima. Some of the intermediate structures between
the initial and final states can be characterized by experimental techniques. Computer
simulations can explore the dynamics of individual states and bring these together to
rationalize the overall process. A novel method based on atomistic structure-based
potentials in combination with the empirical valence bond theory (EVB-SBP) has been
developed and implemented in the Amber package. The method has been successfully
applied to explore various biological processes. The first application of the EVB-SBP
approach involves the study of base flipping in B-DNA. The use of simple structurebased
potentials are shown to reproduce structural ensembles of stable states obtained
by using more accurate force field simulations. Umbrella sampling in conjunction with
the energy gap reaction coordinate enables the study of alternative molecular pathways
efficiently. The main application of the method is the study of the switching mechanism
in a short bistable RNA. Molecular pathways, which connect the two stable states, have
been elucidated, with particular interest to the characterisation of the transition state
ensemble. In addition, NMR experiments have been performed to support the
theoretical findings. Finally, a recent study of large-scale conformational transitions in
protein kinases shows the general applicability of the method to different biomolecules.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Chemistry
Subjects: Q Science > QD Chemistry
Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Depositing User: Library Cataloguing
Date Deposited: 05 Jul 2011 09:38
Last Modified: 14 Aug 2015 13:49

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