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Rational design of selective modulators of skeletal myosin


Project Description

Applications are invited for a PhD studentship funded by Muscular Dystrophy UK (MDUK) starting January 2020 in Dr. Arianna Fornili’s group at Queen Mary University of London and Dr. Julien Ochala’s group at King’s College London.

Research Environment

Queen Mary is a member of the Russell group and is one of the leading research-focused institutions in the UK. We have been ranked 9th among multi-faculty institutions in the UK for research impact in the 2014 Research Excellence Framework (REF) exercise. The School of Biological and Chemical Sciences offers a multi-disciplinary research environment and have approximately 160 PhD students working on projects in the biological, chemical and psychological sciences. Our students have access to a variety of research facilities supported by experienced staff, as well as a range of student support services.

Dr Fornili has unique expertise in the computational study of biomolecular dynamics and in particular of proteins involved in muscle contraction. Recent contributions from the lab include the first theoretical observation of a binding pocket induced by mechanical stress (JCTC, 2019), the development of methods for the prediction of rescue binding pockets in proteins (Bioinformatics, 2018) and the study of the effects of a heart failure drug on cardiac myosin dynamics (PLOS Comp. Biol., 2017). More information can be found at https://afornililab.wordpress.com.

Dr Ochala is a Reader in Physiology at King’s College London. He has unique experience as well as an international reputation in delivering mechanistic muscle studies. He has established a full portfolio of advanced biophysical techniques and continue to publish landmark papers relating to the myosin motor function or cellular mechanics. More information can be found at https://kclpure.kcl.ac.uk/portal/julien.ochala.html.

Training and Development

Our PhD students become part of Queen Mary’s Doctoral College which provides training and development opportunities, advice on funding, and financial support for research. Our students also have access to a Researcher Development Programme designed to help recognise and develop key skills and attributes needed to effectively manage research, and to prepare and plan for the next stages of their career.

The successful candidate will be trained in different modelling techniques, including molecular dynamics simulations, molecular docking and virtual screening. The student will also have the opportunity to learn scientific programming languages for data analysis such as R and Python.

Training for the experimental part of the project will be provided in Dr. Ochala’s lab at King’s College London, where the student will learn how to perform in vitro motility assays and to test myofibre mechanics.

Project Details

The aim of the project is to design and test small molecules that can selectively target skeletal myosin, a key component of the molecular machinery involved in muscle contraction. The main outcome will be a new set of potential myosin modulators, that is compounds that can bind to myosin and modify its function, to be used as leads in the development of drugs for severe muscle diseases such as nemaline myopathy.

The therapeutic potential of myosin modulators has been recently demonstrated by the discovery of cardiac-selective modulators for the treatment of heart conditions such as heart failure or hypertrophic cardiomyopathy. The expected advantages of this type of drugs over more traditional approaches are a reduction of side effects and the possibility to develop more personalised drug therapies using a spectrum of molecules to finely tune the activity of the target.

In this project, a structure-based approach will be adopted for the development of new myosin modulators, where potential candidates will be identified by using computational techniques such as molecular dynamics simulations, molecular docking and virtual screening, and subsequently tested using in vitro motility assays.

Eligibility

Applications are welcome from outstanding European/UK students with or expecting to obtain at least a masters or first/upper second class honours degree in Chemistry, Pharmaceutical Chemistry, Biochemistry, Physics, Biophysics or related disciplines. Previous experience in molecular modelling/simulation is essential, previous experience in computer programming and/or experimental biophysical techniques is a plus.

Applicants from outside of the UK are required to provide evidence of their English language ability: https://www.qmul.ac.uk/international-students/englishlanguagerequirements/postgraduateresearch/

Application

Before submitting a formal application online, please contact Dr. Fornili () and include your CV, your academic transcripts, a cover letter explaining eligibility and interest in the project and the contact details of two academic referees. Formal applications must be submitted through our online form by the 14th October 2019.

The School of Biological and Chemical Sciences is committed to promoting diversity in science; we have been awarded an Athena Swan Bronze Award. We positively welcome applications from underrepresented groups.
http://hr.qmul.ac.uk/equality/
https://www.qmul.ac.uk/sbcs/about-us/athenaswan/

Funding Notes

This studentship is open to UK/EU applicants and is funded by Muscular Dystrophy UK (MDUK). It will cover tuition fees, and provide an annual tax-free maintenance allowance for 4 years at the Research Council rate (£17,009 in 2019/20).

References

• M. Tiberti, B.-D. Lechner, A. Fornili. Binding Pockets in Proteins Induced by Mechanical Stress. J Chem Theor Comp 15 (2019) 1.
• M. Tiberti, A. Pandini, F. Fraternali, A. Fornili: In silico identification of rescue sites by double force scanning, Bioinformatics 34 (2018) 207.
• S. Hashem, M. Tiberti, A. Fornili: Allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil, PLoS Comp. Biol. 13 (2017) e1005826.
• Jungbluth H, Treves S, Zorzato F, Sarkozy A, Ochala J, Sewry C, Phadke R, Gautel M, Muntoni F The congenital myopathies – inherited disorders of excitation-contraction coupling and muscle contraction. Nat Rev Neurol. 14 (2018) 151.
• Chan C, Fan J, Messer AE, Marston SB, Iwamoto H, Ochala J. Myopathy-inducing mutation H40Y in ACTA1 hampers actin filament structure and function. Biochim Biophys Acta. 1862 (2016) 1453.
• Lindqvist J, Levy Y, Pati-Alam A, Hardeman EC, Gregorevic P, Ochala J. Modulating myosin restores muscle function in a mouse model of nemaline myopathy. Ann Neurol. 79 (2016) 717.
• Ochala J, Sun YB. Novel myosin-based therapies for congenital cardiac and skeletal myopathies. J Med Genet. 53 (2016) 651.

How good is research at Queen Mary University of London in Chemistry?

FTE Category A staff submitted: 14.00

Research output data provided by the Research Excellence Framework (REF)

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