Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.692857
Title: Membrane protein mechanotransduction : computational studies and analytics development
Author: Dahl, Anna Caroline E.
ISNI:       0000 0004 5920 3056
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2014
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Abstract:
Membrane protein mechanotransduction is the altered function of an integral membrane protein in response to mechanical force. Such mechanosensors are found in all kingdoms of life, and increasing numbers of membrane proteins have been found to exhibit mechanosensitivity. How they mechanotransduce is an active research area and the topic of this thesis. The methodology employed is classical molecular dynamics (MD) simulations. MD systems are complex, and two programs were developed to reduce this apparent complexity in terms of both visual abstraction and statistical analysis. Bendix detects and visualises helices as cylinders that follow the helix axis, and quantifies helix distortion. The functionality of Bendix is demonstrated on the symporter Mhp1, where a state is identified that had hitherto only been proposed. InterQuant tracks, categorises and orders proximity between parts of an MD system. Results from multiple systems are statistically interrogated for reproducibility and significant differences at the resolution of protein chains, residues or atoms. Using these tools, the interaction between membrane and the Escherichia coli mechanosensitive channel of small conductance, MscS, is investigated. Results are presented for crystal structures captured in different states, one of which features electron density proposed to be lipid. MD results supports this hypothesis, and identify differential lipid interaction between closed and open states. It is concluded that propensity for lipid to leave for membrane bulk drives MscS state stability. In a subsequent study, MscS is opened by membrane surface tension for the first time in an MD setup. The gating mechanism of MscS is explored in terms of both membrane and protein deformation in response to membrane stretch. Using novel tension methodology and the longest MD simulations of MscS performed to date, a molecular basis for the Dashpot gating mechanism is proposed. Lipid emerges as an active structural element with the capacity to augment protein structure in the protein structure-function paradigm.
Supervisor: Sansom, Mark S. P. Sponsor: Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.692857  DOI: Not available
Keywords: Life Sciences ; Biochemistry ; Bioinformatics (biochemistry) ; Computational biochemistry ; Molecular biophysics (biochemistry) ; Cell Biology (see also Plant sciences) ; Biology ; Microbiology ; Nano-biotechnology ; Numerical analysis ; Statistical mechanics ; structure of matter (mathematics) ; Protein chemistry ; MscS ; mechanosensitive channel of small conductance ; mechanotranduction ; mechanosensation ; Bendix ; InterQuant ; molecular dynamics ; integral membrane protein ; membrane protein ; E.coli
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