Experiments to find out how changes at the molecular level are causing this resistance are difficult and, so far, have not been done. Now, however, Peter Coveney and co-workers from UCL and Queen Mary, University of London have investigated the problem using computer modelling techniques. Their findings are amongst several outputs of the UK e-Science programme that are discussed in a special Theme Issue of Philosophical Transactions of the Royal Society A* which is published on 15 August.
They took experimental data gathered from other organisms to build computer models of the sites where drug molecules interact with an organism's protein molecules. They then ran simulations and visualised what happens when a drug molecule approaches each site for both normal and drug-resistant strains of S. pneumoniae.
The simulations and visualisations exploited highly scalable parallel code running on the UK's national supercomputing facilities. "Without the use of e-Science methods, they would have taken months to perform and quite probably would never have been done. With these new methods, each simulation took just 12 hours," says Professor Coveney. So far, life scientists have had limited access to and interest in such high performance computing resources; with Grid computing, these resources are becoming more readily accessible.
Professor Coveney and colleagues could see that a very small, but subtle, difference in structure between the normal and drug resistant strains was to blame for the drug resistance. In the normal strain, a drug molecule binds tightly to the site, but in the drug resistant strain it approaches and then drifts slowly away. If the results of the simulation are borne out by experiment, they could point the way to new drugs to combat disease.
*Large-scale molecular dynamics simulation of native and mutant dihydropteroate synthase-sulfanimide complexes suggests the basis of dihydropteroate synthase drug resistance by F.Giordanetto, P. W. Fowler, M Saqi and P. V. Coveney Philosophical Transactions of the Royal Society A 363 1833 (15 August 2005) http://www.pubs.royalsoc.ac.uk/phil_trans_phys_scientificgrid.shtml
For another story from the Theme Issue go to: http://www.rcuk.ac.uk/escience/news/flowsim.asp
Contacts
Professor Peter Coveney, UCL tel. 020 7679 4560 e-mail: P.V.Coveney@ucl.ac.uk
Philip Fowler, UCL tel. 020 7679 5300 e-mail: philip.fowler@ucl.ac.uk
Judy Redfearn, e-Science communications officer, e-Science Core Programme, EPSRC tel. 01793 444314 e-mail: judy.redfearn@epsrc.ac.uk
Notes for editors
1. e-Science is the very large scale science that can be carried out by pooling access to very large digital data collections, very large scale computing resources and high performance visualisation held at different sites.
2. A computing grid refers to geographically dispersed computing resources that are linked together by software known as middleware so that the resources can be shared. The vision is to provide computing resources to the consumer in a similar way to the electric power grid. The consumer can access electric or computing power without knowing which power station or computer it is coming from.
3. The UK e-Science Programme is a coordinated £230M initiative involving all the Research Councils and the Department of Trade and Industry. It has also leveraged industrial investment of £30M. The Engineering and Physical Sciences Research Council manages the Core e-Science Programme, which is developing generic technologies, on behalf of all the Research Councils.
4. The UK e-Science Programme as a whole is fostering the development of IT and grid technologies to enable new ways of doing faster, better or different research, with the aim of establishing a sustainable, national e-infrastructure for research and innovation. Further information at http://www.rcuk.ac.uk/escience/