Computational approaches to understanding the mechanosensitive Piezo1 channel activation mechanism

Project description

Mechanical forces such as shear stress and radial stretch regulate vascular functions of endothelial cells eg endothelial cell alignment to blood flow and endothelium-dependent vasodilation. For these reasons, mechanical forces are important in many cardiovascular diseases. This project will focus on Piezo1 channel that is a critical mechanical sensor for shear stress in endothelial cells. 

Piezo1 function is to permeate ions in response to mechanical stimuli. Single mutations on Piezo1 have also been shown to result in disorders in humans. Whilst a number of new 3D structures of Piezo1 that were published recently increased our understanding of Piezo1 function, fundamental aspects of Piezo1 activation and ion transport remain largely unknown. Computational approaches, such as molecular simulations, can provide a ‘computational microscope’ enabling us to study proteins at the molecular level and to make predictions to test new hypotheses. Importantly, multi-scale molecular simulations (i.e. coarse-grained and all-atom simulations) can be used to investigate in detail the molecular mechanisms and the energetics by which ion channels function. Combining the models/hypotheses derived from the computer simulations with lab-based studies offers an opportunity for major progress in understanding how Piezo1 functions.

In this project, the student will use multi-scale simulations and molecular modelling (Kalli group) to simulate the new Piezo1 structures in model membranes containing a full complement of phospholipids. The student will use these simulations to examine the Piezo1 activation mechanism and to investigate the role of the membrane environment in regulating Piezo1 function. The models derived from the computer simulations will be evaluated/refined experimentally, using cell-based assays and molecular biology techniques in Beech/Shi groups. The dynamic information about Piezo1 from this study will enable us to increase our understanding for the mechanism of action of this very important channel protein.

The student will be a part of a multidisciplinary team that already studies Piezo1 and has extensive experience on how to study Piezo1 channel using both advanced computational and lab-based approaches. This project will suite anyone wishing to learn a range of complementary skills, including both computational and lab-based skills.

References:

1. Kalli AC et al., Molecular dynamics simulations of the bacterial UraA H+-Uracil symporter in lipid bilayers reveal a closed state and a selective interaction with cardiolipin. PLoS Comput. Biol. 2015;11(3):e1004123.

2. Li J et al., Piezo1 integration of vascular architecture with physiological force. Nature. 2014, 515(7526):279-82.

Entry requirements

This project is available immediately to both Home/EU rate applicants and International applicants who are able to self-fund their studies. Students must be able to provide the appropriate level of fees based on their fee status plus laboratory consumables costs per year. This is in addition to the provision of personal living expenses.

You should hold a first degree equivalent to at least a UK upper second class honours degree in a relevant subject.

Candidates whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study, the Faculty minimum requirements are:

• British Council IELTS - score of 6.5 overall, with no element less than 6.0
• TOEFL iBT - overall score of 92 with the listening and reading element no less than 21, writing element no less than 22 and the speaking element no less than 23.

Applicants with sufficient funding must still undergo formal interview prior to acceptance in order to demonstrate scientific aptitude and English language capability.

How to apply

Applications can be made at any time. Potential applicants are welcome to contact Antreas Kalli with informal enquiries about this research project.

To formally apply for this project applicants should complete a Faculty Scholarship Application form and send this alongside a full academic CV, degree transcripts (or marks so far if still studying) and degree certificates to the Faculty Graduate School. 

We also require 2 academic references to support your application. Please ask your referees to send these references on your behalf, directly by email.

If you have already applied for other scholarships using the Faculty Scholarship Application form you do not need to complete this form again. Instead you should email to inform us you would like to be considered for this scholarship project.