Computational modelling of myosin mutants for the treatment of congenital myopathies
Research Group: Chemistry
Number of Students: 1
Length of Study in Years: 3.5 Years
Full-time Project: yes
This studentship is fully funded via the UKRI EPSRC Doctoral Training Programme for 3.5 years and includes a stipend (currently £17,609 in 2021/2022) and Fees.
Congenital myopathies are inherited disorders affecting skeletal muscles, and resulting in varying severities (estimated prevalence 1:50,000)1. No cure exists to date and the related medical expenses and economic consequences are vast. Several genes have been found to be involved and they all lead to cellular hyper- or hypo-contractility. Recent research on cardiovascular disease has shown that it is possible to restore normal contractility by targeting cardiac muscle proteins with small molecule modulators2. This approach has been less explored for skeletal muscle disorders and it will be the focus of the present project. Our aim will be to use computational methods to model pathogenic mutations of skeletal myosin, a key protein whose motions drive the whole contraction process in muscles. Modelling performed in the lab on wild type myosin3-4 indicates that it is possible to design compounds that can selectively target specific conformations and isoforms of the protein, which are both necessary conditions to obtain safe and effective drugs. However, mutations can significantly affect the structure and dynamics of a protein, and a characterisation of these mutants at the atomistic level is currently missing. A combination of homology modelling, Molecular Dynamics simulations and virtual screening will be used to model the mutants and characterise their druggability. The resulting atomistic models of the binding sites will be used for future studies in collaboration with Dr Julien Ochala (KCL/University of Denmark, https://bmi.ku.dk/english/research/xlab/), which will be focused on the rational design of compounds that can target the mutants and restore normal contractility.
This year UKRI announced that there will be a limited number of studentships for international students available. International applicants are encouraged to apply but should note that studentship awards will be subject to eligibility and the availability of funding.
To be classed as a home student, applicants must meet the following criteria:
- Be a UK National (meeting residency requirements), or
- Have settled status, or
- Have pre-settled status (meeting residency requirements), or
- Have indefinite leave to remain or enter
If a candidate does not meet the criteria above, they would be classified as an international student.
- The minimum requirement for this studentship opportunity is a good Honours degree (minimum 2(i) honours or equivalent) or MSc/MRes in a relevant discipline.
- If English is not your first language, you will require a valid English certificate equivalent to IELTS 6.5+ overall with a minimum score of 6.0 in Writing and 5.5 in all sections (Reading, Listening, Speaking).
- Candidates are expected to start from September 2022
Application Deadline - 30th January
Please use the link below to apply:
SPCS Academics: Dr Arianna Fornili