Action! Modelling DNA nano-machines for deciphering their molecular mechanisms

This computational PhD project aims to model experimental high-resolution structural snapshots of essential viral DNA-nano-machines, including helicases and DNA packaging motors for unravelling how they work.

Viruses are the most abundant biological agents on our planet, infecting organisms across all domains of life. They affect humans directly, through infections and associated disorders, and also indirectly through impact on animals, plants and bacterial populations. The replication of the viral genome and its packaging into a capsid are essential to the viral life cycle and are mediated by nucleic acid-processing protein machines, all fuelled by energy derived from NTP hydrolysis. While there are structural and functional similarities, these machines have evolved to perform different tasks and many of them are still poorly characterised.

The research will address the knowledge gap in the molecular mechanisms of several selected protein-nucleic acid machines, for which accurate X-ray structures have already been obtained in Antson lab (YSBL, Chemistry Department). One such machine is the papillomavirus E1 helicase, which unwinds dsDNA during viral replication. Another machine, targeted in this project, is the DNA packaging motor present in tailed bacteriophages and evolutionarily related herpes viruses (such as Cytomegalovirus). The machine translocates viral DNA, replicated within the host cell, into an empty pre-formed viral capsid. In spite of detailed structural information, it is still unknown how exactly these machines work. That’s why the computer simulations planned in this project will bring a significant advance.

The work will be in the group of Dr. Agnes Noy (www.agnenoy.cat) and also carried out in collaboration with the group of Prof. Fred Antson where additional PhD students and post-doctoral research assistants are already performing complementary biophysical and biochemical experiments using X-ray crystallography, Cryo-EM, NMR and site-directed mutagenesis techniques.
In addition to a fundamental impact, the research will contribute to the healthcare and biotechnology sectors. Helicases from papillomaviruses and DNA packaging motors from herpesviruses are attractive targets for drugs against some of the most prevalent viral diseases in animals and man. Furthermore, the group of Fred Antson are starting to develop these proteins for DNA sequencing and other nano-technological applications. Thus, this studentship will tackle the challenges of “developing novel therapies” and “manufacturing the future” within the strategic areas of healthcare and biotechnology as has been recognised by EPSRC and by the University of York.

This project will give the PhD student a unique skill set as she/he will obtain direct expertise in state-of-the-art computer simulation techniques using modern computational approaches including AMBER and GROMACS; by working on some of the most powerful supercomputers available, they will acquire excellent IT skills that will include knowledge in Linux/Unix operating systems and in programming languages like Python, Fortran or C++. In addition, the project provides a unique opportunity to working in a truly multidisciplinary environment. Finally, the studentship will benefit from and will contribute to cross-departmental links between York Structural Biology Laboratory (YSBL) and the Biological Physical Sciences Institute (BPSI) at the University of York. With the current high profile of biological physics within the University, and internationally, we anticipate that this proposal is likely to generate further research collaborations, both nationally and internationally.

The PhD studentship will be registered in Physics, with the student having access to facilities both in Physics and YSBL.