Molecular dynamics analysis of mRNA capping: Characterising the activation mechanisms of the mammalian capping enzymes

Lead Research Organisation: University of Dundee
Department Name: School of Life Sciences

Abstract

mRNA capping is vital for the regulation of genes in eukaryotic organisms. This capping is activated downstream of c-Myc, a major oncoprotein overexpressed in over 50% of human cancers, therefore, mRNA capping is a promising target for cancer therapeutics. The Capping Enzyme carries out the first two steps in this process. Many questions remain about its activation and regulation, limiting our ability to design drugs that target it. It is activated by binding to the phosphorylated C-terminal Domain of RNA Polymerase II. However, the molecular details of this activation mechanism have been elusive using conventional biochemical techniques.
I will address this problem from a new angle by using molecular dynamics simulations to study the conformational changes that occur upon C-terminal Domain binding. Further computational and biophysical analysis will be performed to characterise the interaction surface and catalytic core. An interdisciplinary collaboration with the Cowling lab will yield experimental evidence to support these findings.


Key Words and Skills:


Questions:

1. Explain interdisciplinary interface: Yes, it talks about collaboration between computational biophysics and experimental biology

2. Does project require significant amount of quantitative skills? YES

3. Does project require significant amount of whole organism physiology skills? NO

Publications

10 25 50
 
Description Academy of Medical Sciences Policy Internship Available to MRC-Funded PhD Students
Geographic Reach National 
Policy Influence Type Participation in a national consultation
Impact I will be undertaking an internship at the Academy of Medical Sciences (AMS) in London starting in April 2019 and funded as part of my MRC PhD studentship. I will spend 3 months at the AMS central London offices as described on their internships page: https://acmedsci.ac.uk/about/administration/internship-schemes. During this time I will gain a fundamental understanding of the role of science policy and its impact on academic and commercial research. I will also have a unique opportunity to discuss the key issues that are affecting medical science today with the UK's most eminent medical scientists and health stakeholders. I will also provide the Academy with first-hand experience in Medical Scientific Research, making myself a useful member of the policy team. After the internship I will have built up key skills in communicating and disseminating scientific information. I will bring this experience back to the University of Dundee, using the skills gained in my ongoing doctoral research.
URL https://acmedsci.ac.uk/about/administration/internship-schemes
 
Description MRC Flexible Supplement Fund Award 2016/2017 (Conference Travel Grant)
Amount £450 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 07/2017 
End 07/2017
 
Description MRC Flexible Supplement Fund Award 2018/2019 (Awarded For AMS-MRC Policy Internship)
Amount £5,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2019 
End 07/2019
 
Description Teaching Python Programming to Undergraduate Physics Students at the University of Dundee 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact I worked as an assistant in tutorial workshops for a semester, teaching second-year Physics undergraduate students at the University of Dundee. The course was an introduction to Python and Matlab programming. I made substantial contributions to the tutorials, helping many of the students with any difficulties they had with the theory or implementation of the material they were learning. By the end of the semester the majority of the students had a strong grasp of programming. Over 80% of the class obtained an A or higher in this module, a notable increase from previous years. In addition, being a biologist teaching physics students, I introduced them to the relevance of using programming and physics in biological research.
Year(s) Of Engagement Activity 2017