The Biophysics of Force Sensing Membrane Proteins by High-Speed Atomic Force Microscopy

High-speed atomic force microscopy (HS AFM) captures 3D videos of molecules on the nanoscale at rates of up to 20 frames per second in liquid. By filming proteins important in biology we can capture complex behaviour and structural dynamics at high resolution. Within cell membranes, mechanosensitive channels are found throughout all forms of life acting as sensors for a number of systems including touch, hearing, gravity, osmotic pressure and cardiovascular regulation. These force sensitive channels open upon specific mechanical activation allowing certain molecules to enter or exist cells. This PhD project will use state-of-the-art HS-AFM to directly watch conformational dynamics of single membrane proteins the at the nanoscale in response to force. <br /> <br /> In cells these proteins are vital for many physiological functions consequently problems such as genetic mutations have been implicated in a number of severe human diseases. On the other hand, bacteria use these channels to regulate their internal turgor cytoplasmic pressure in response to rapid osmotic changes in their environment. Despite their importance, the molecular mechanism behind how these proteins respond to membrane tension is unknown. Developing an understanding for these mechanisms will help resolve the molecular basis of disease and give insight into potential drug targets to fight antimicrobial resistant bacteria.

<table align="left" cellpadding="0" cellspacing="0" hspace="0" vspace="0"> <tbody> <tr> <td> <p>HS-AFM&nbsp;allows simultaneous sub&nbsp;nanometre&nbsp;video rate imaging whilst varying forces&nbsp;and environmental conditions.&nbsp; This study will use HS-AFM to video the structural dynamics of single molecules while applying varying amounts of force and changing environmental conditions.&nbsp;As a newly developed&nbsp;technique this study has a wide scope to develop new methods and analysis approaches. Experiments will&nbsp;focus on understanding&nbsp;the&nbsp;structural dynamics&nbsp;to&nbsp;develop&nbsp;physical&nbsp;models&nbsp;of how different molecules sense force. This research will be&nbsp;performed in&nbsp;collaborations across the Bragg and Astbury Centres between the Heath and Pliotas&nbsp;Lab in&nbsp;the&nbsp;School of Physics &amp; Astronomy and School of Biomedical Sciences,&nbsp;who are&nbsp;experts in&nbsp;the HS-AFM and structural biophysics of&nbsp;mechanosensitive ion channels.</p> <ol type="1"> <li>Heath, G.R., Kots, E., Robertson, J.L.&nbsp;<em>et al.</em>&nbsp;Localization atomic force microscopy.&nbsp;<em>Nature&nbsp;</em><strong>594,&nbsp;</strong>385&ndash;390 (2021).&nbsp;<a href="https://doi.org/10.1038/s41586-021-03551-x">https://doi.org/10.1038/s41586-021-03551-x</a></li> <li>Heath, G.R., Scheuring, S. High-speed AFM height spectroscopy reveals &micro;s-dynamics of unlabeled biomolecules.&nbsp;<em>Nat Commun</em>&nbsp;<strong>9,&nbsp;</strong>4983 (2018).&nbsp;<a href="https://doi.org/10.1038/s41467-018-07512-3">https://doi.org/10.1038/s41467-018-07512-3</a></li> <li>Kapsalis, C., Wang, B., El Mkami, H.&nbsp;<em>et al.</em>&nbsp;Allosteric activation of an ion channel triggered by modification of mechanosensitive nano-pockets.&nbsp;<em>Nat Commun</em>&nbsp;<strong>10,&nbsp;</strong>4619 (2019).&nbsp;<a href="https://doi.org/10.1038/s41467-019-12591-x">https://doi.org/10.1038/s41467-019-12591-x</a></li> </ol> </td> </tr> </tbody> </table> <div style="clear:both;">&nbsp;</div>

<p>Formal applications for research degree study should be made online through the&nbsp;<a href="https://www.leeds.ac.uk/research-applying/doc/applying-research-degrees">University&#39;s website</a>. Please state clearly in the Planned Course of Study section that you are applying for<em><strong> PHD Physics &amp; Astronomy FT</strong></em> and in the research information section&nbsp;that the research degree you wish to be considered for is <em><strong>The Biophysics of Force Sensing Membrane Proteins by High-Speed Atomic Force Microscopy&nbsp;</strong></em>as well as <a href="https://eps.leeds.ac.uk/physics/staff/6132/dr-george-heath">Dr George Heath</a>&nbsp;as your proposed supervisor.</p> <p>If English is not your first language, you must provide evidence that you meet the University&#39;s minimum English language requirements (below).</p> <p style="margin-bottom:11px"><em>As an international research-intensive university, we welcome students from all walks of life and from across the world. We foster an inclusive environment where all can flourish and prosper, and we are proud of our strong commitment to student education. Across all Faculties we are dedicated to diversifying our community and we welcome the unique contributions that individuals can bring, and particularly encourage applications from, but not limited to Black, Asian, people who belong to a minority ethnic community, people who identify as LGBT+ and people with disabilities. Applicants will always be selected based on merit and ability.</em></p> <p class="MsoNoSpacing">Applications will be considered on an ongoing basis. &nbsp;Potential applicants are strongly encouraged to contact the supervisors for an informal discussion before making a formal application. &nbsp;We also advise that you apply at the earliest opportunity as the application and selection process may close early, should we receive a sufficient number of applications or that a suitable candidate is appointed.</p> <p>Please note that you must provide the following documents at the point you submit your application:</p> <ul> <li>Full Transcripts of all degree study or if in final year of study, full transcripts to date</li> <li>Personal Statement outlining your interest in the project</li> <li>CV</li> <li>Funding information including any alternative sources of funding that you are applying for or if you are able to pay your own fees and maintenance</li> </ul>

Applicants to research degree programmes should normally have at least a first class or an upper second class British Bachelors Honours degree (or equivalent) in an appropriate discipline. The criteria for entry for some research degrees may be higher, for example, several faculties, also require a Masters degree. Applicants are advised to check with the relevant School prior to making an application. Applicants who are uncertain about the requirements for a particular research degree are advised to contact the School or Graduate School prior to making an application.

The minimum English language entry requirement for research postgraduate research study is an IELTS of 6.0 overall with at least 5.5 in each component (reading, writing, listening and speaking) or equivalent. The test must be dated within two years of the start date of the course in order to be valid. Some schools and faculties have a higher requirement.

<p style="margin-bottom:12px"><strong>Self-Funded or externally sponsored students are welcome to apply.</strong></p> <p><strong>UK</strong>&nbsp;&ndash;&nbsp;The&nbsp;<a href="https://phd.leeds.ac.uk/funding/209-leeds-doctoral-scholarships-2022">Leeds Doctoral Scholarships</a> and <a href="https://phd.leeds.ac.uk/funding/234-leeds-opportunity-research-scholarship-2022">Leeds Opportunity Research Scholarship</a> are available to UK applicants. The&nbsp;<a href="https://phd.leeds.ac.uk/funding/102-bell-burnell-scholarship-award-awarded-by-the-iop">Bell Burnell Scholarship Award</a>&nbsp;is available to support applicants who are from groups that are currently under-represented in physics (awarded by the IOP).&nbsp; <a href="https://phd.leeds.ac.uk/funding/60-alumni-bursary">Alumni Bursary</a> is available to graduates of the University of Leeds.</p> <p><strong>Non-UK</strong> &ndash; The&nbsp;<a href="https://phd.leeds.ac.uk/funding/102-bell-burnell-scholarship-award-awarded-by-the-iop">Bell Burnell Scholarship Award</a>&nbsp;is available to support applicants who are from groups that are currently under-represented in physics (awarded by the IOP).&nbsp; &nbsp;The&nbsp;<a href="https://phd.leeds.ac.uk/funding/48-china-scholarship-council-university-of-leeds-scholarships-2021">China Scholarship Council - University of Leeds Scholarship</a>&nbsp;is available to nationals of China. The&nbsp;<a href="https://phd.leeds.ac.uk/funding/73-leeds-marshall-scholarship">Leeds Marshall Scholarship</a>&nbsp;is available to support US citizens. <a href="https://phd.leeds.ac.uk/funding/60-alumni-bursary">Alumni Bursary</a> is available to graduates of the University of Leeds.</p> <p><strong>Important:</strong>&nbsp; Any costs associated with your arrival at the University of Leeds to start your PhD including flights, immigration health surcharge/medical insurance and Visa costs are <strong>not</strong> covered under this studentship.</p> <p>Please refer to the <a href="https://www.ukcisa.org.uk/">UKCISA</a> website for information regarding Fee Status for Non-UK Nationals.</p>

<p>For further information on the project do not hesitate to contact any of the project supervisors by email (George Heath&nbsp;<a href="mailto:G.R.Heath@leeds.ac.uk">G.R.Heath@leeds.ac.uk</a>&nbsp;and Christos Pliotas&nbsp;<a href="mailto:C.Pliotas@leeds.ac.uk">C.Pliotas@leeds.ac.uk</a>). We are always happy to discuss scientific questions with pro-active candidates. For details on how to apply and admin arrangements, please contact Doctoral College Admissions by email:&nbsp;<a href="mailto:EMAIL@leeds.ac.uk">m</a><a href="mailto:maps.pgr.admissions@leeds.ac.uk">aps.pgr.admissions@leeds.ac.uk</a>.</p>