RITS Case Studies
- Centre for Innovation expertise benefits tsunami modelling at UCL
- Using new computer architecture to help improve cancer treatments
- Observing the cataclysmic universe: a research data case study
- Crime scene DNA analysis: assessing the evidence
- HemeLB: vascular modelling and blood flow simulation
- Restructuring and extending DCPROGS, an established suite for the analysis of single ion channel data
- How UCL’s new research equipment catalogue service was developed
Restructuring and extending DCPROGS, an established suite for the analysis of single ion channel data
Published: Dec 9, 2013 11:08:00 AM
Published: Oct 16, 2013 11:48:00 AM
Published: Oct 2, 2013 4:33:00 PM
Published: Jul 24, 2013 4:47:00 PM
Published: Jul 3, 2013 11:48:34 AM
Using new computer architecture to help improve cancer treatments
24 July 2013
Professor Francesco Gervasio of UCL’s Department of Chemistry used the Emerald supercomputer (built in partnership with the Centre for Innovation) to simulate the effect of gene mutations linked to the spread of cancer. His research could help develop more robust and effective cancer treatments.
Epidermal Growth Factor Receptor (EGFR) is a protein that causes
cell growth and differentiation. Gene mutations
that lead to EGFR over-activity have been associated with a number of cancers,
particularly lung cancer. Not surprisingly, EGFR is the target of a rapidly
expanding class of anti-cancer drugs.
Epidermal growth factor receptor (EGFR), complexed with epidermal growth factor (magenta-coloured)
Recent efforts in treating cancer have focused on a part of the EGFR: the tyrosine kinase enzyme, which functions like an ‘off’ and ‘on’ switch for many cellular functions. Mutations of the EGFR kinase can cause it to become stuck in the ‘on’ or active position, causing tumour growth. Certain tyrosine kinase inhibitors (TKIs) have proven to be successful in slowing down tumour growth. Unfortunately, many cancer patients develop resistance to them.
Researchers need to understand more about common EGFR kinase mutations such as T790M and L858R, so as to develop more effective inhibitor drugs for cancer patients. Not much is known about these mutations, especially at an atomic level, but it is believed that changes to the transition between their active (‘on’) and inactive (‘off’) states are linked to their cancer-causing potential.
Because proteins are very flexible and can easily change conformation, simulating these transitions requires enormous computational effort. Recent research – using very complex molecular dynamics simulations (involving billions of steps) and conducted on multi-million dollar specialised supercomputer Anton – gave further evidence of how the kinase mutations affect the protein’s conformation. Even with this vast computational power, the researchers only observed two conformational changes, which were barely sufficient to grasp the full impact caused by the mutations.
What we did
Francesco’s work took advantage of recent
progress in molecular dynamics and the availability of specialised computer
hardware to try and understand more about EGFR kinase’s conformational changes,
in particular the interaction between the mutations T790M and L858R. He chose to simulate this double mutant,
along with both of the single mutants and a control mutant.
Professor Francesco Gervasio seated in UCL's Academic Staff Common Room
Francesco used an extremely efficient sampling technique called ‘parallel-tempered metadynamics’ to study the dynamics of the kinase very close to its equilibrium state. Here, he could observe a large number of small conformational transitions that occur in a very short timescale.
He used the GROMACS molecular dynamics software with the
PLUMED metadynamics plug-in, adapted to run on the Centre for Innovation’s Emerald high performance computer system.
uses specialised, highly parallelised GPU architecture (Graphical Processor
Units, similar to the video cards used to accelerate the speed of the display
on desktop PCs). Emerald was able to
carry out the simulations much more quickly than would be possible on a machine
with standard architecture (like Anton).
Although we also have a PRACE (Partnership for Advanced Computing in Europe) allocation of 24 million CPU hours, we can use this up very easily. Each simulation uses multiple replicas (at different temperatures) and so it has billions of sampling steps. The CPU time this takes is greatly reduced using Emerald’s GPU architecture because the code can be very highly parallelised, making it much more efficient.
Professor Francesco Gervasio, UCL Chemistry
Francesco’s previous research group in Spain had purchased their own high performance system - consisting of rack-mounted servers with cheap PC graphics cards. It was expensive and difficult to keep running, due to the heat generated by the processors.
The system got so hot that at least one graphics card broke every month. People think computing power is now very cheap, but they don’t realise the true costs of a system like this.
Professor Francesco Gervasio, UCL Chemistry
In contrast, Emerald has a specialised cooling system and dedicated staff to support and maintain it, with expert GPU developers to assist researchers with migrating their codes to the new architecture. UCL has partnered with 3 other universities and the Science & Technology Facilities Council (STFC) to form the Consortium which funds the Centre for Innovation, sharing the costs of this infrastructure.
Results / impact of the work
Francesco’s results have helped shed new light on how mutations of the EGFR kinase affect its likelihood of causing tumour growth.
This new knowledge is important because it can be used to devise new strategies for developing tyrosine kinase inhibitors that are less susceptible to the development of drug resistance.
- Professor Francesco Gervasio's page at UCL Chemistry
- Francesco's published article on his work in Proceedings of the National Academy of Sciences of the United States of America (PNAS)
- The PLUMED plugin for free-energy calculations with molecular dynamics
- Science & Technology Facilities Council
- PRACE (Partnership for Advanced Computing in Europe)
- To learn more about the Centre for Innovation and to find out about partnership opportunities, visit the CfI website
- To find out about help available to researchers at UCL, visit our Help for UCL researchers page