Membrane protein mechanotransduction: computational studies and analytics development
<p>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 mechanotra...
| Main Authors: | , |
|---|---|
| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
2014
|
| Subjects: |
| _version_ | 1797073089936228352 |
|---|---|
| author | Dahl, A Anna Caroline E. Dahl |
| author2 | Sansom, M |
| author_facet | Sansom, M Dahl, A Anna Caroline E. Dahl |
| author_sort | Dahl, A |
| collection | OXFORD |
| description | <p>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.</p> <p>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. <em>Bendix</em> 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. <em>InterQuant</em> 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.</p> <p>Using these tools, the interaction between membrane and the <em>Escherichia coli</em> 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.</p> <p>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 <em>Dashpot</em> gating mechanism is proposed. Lipid emerges as an active structural element with the capacity to augment protein structure in the protein structure-function paradigm.</p> |
| first_indexed | 2024-03-06T23:17:00Z |
| format | Thesis |
| id | oxford-uuid:67798647-8ed5-46e0-bde9-c71235fe70ba |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:17:00Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | oxford-uuid:67798647-8ed5-46e0-bde9-c71235fe70ba2022-03-26T18:38:28ZMembrane protein mechanotransduction: computational studies and analytics developmentThesishttp://purl.org/coar/resource_type/c_db06uuid:67798647-8ed5-46e0-bde9-c71235fe70baCell Biology (see also Plant sciences)Protein chemistryMicrobiologyBioinformatics (biochemistry)Computational biochemistryMolecular biophysics (biochemistry)BiochemistryBiologyStatistical mechanics,structure of matter (mathematics)Nano-biotechnologyNumerical analysisLife SciencesEnglishOxford University Research Archive - Valet2014Dahl, AAnna Caroline E. DahlSansom, M<p>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.</p> <p>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. <em>Bendix</em> 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. <em>InterQuant</em> 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.</p> <p>Using these tools, the interaction between membrane and the <em>Escherichia coli</em> 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.</p> <p>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 <em>Dashpot</em> gating mechanism is proposed. Lipid emerges as an active structural element with the capacity to augment protein structure in the protein structure-function paradigm.</p> |
| spellingShingle | Cell Biology (see also Plant sciences) Protein chemistry Microbiology Bioinformatics (biochemistry) Computational biochemistry Molecular biophysics (biochemistry) Biochemistry Biology Statistical mechanics,structure of matter (mathematics) Nano-biotechnology Numerical analysis Life Sciences Dahl, A Anna Caroline E. Dahl Membrane protein mechanotransduction: computational studies and analytics development |
| title | Membrane protein mechanotransduction: computational studies and analytics development |
| title_full | Membrane protein mechanotransduction: computational studies and analytics development |
| title_fullStr | Membrane protein mechanotransduction: computational studies and analytics development |
| title_full_unstemmed | Membrane protein mechanotransduction: computational studies and analytics development |
| title_short | Membrane protein mechanotransduction: computational studies and analytics development |
| title_sort | membrane protein mechanotransduction computational studies and analytics development |
| topic | Cell Biology (see also Plant sciences) Protein chemistry Microbiology Bioinformatics (biochemistry) Computational biochemistry Molecular biophysics (biochemistry) Biochemistry Biology Statistical mechanics,structure of matter (mathematics) Nano-biotechnology Numerical analysis Life Sciences |
| work_keys_str_mv | AT dahla membraneproteinmechanotransductioncomputationalstudiesandanalyticsdevelopment AT annacarolineedahl membraneproteinmechanotransductioncomputationalstudiesandanalyticsdevelopment |