1. c.woods@soton.ac.uk Investigating Protein Conformational Change on a Distributed Computing Cluster Christopher Woods Jeremy Frey Jonathan Essex University of Southampton Comb e chem

2. c.woods@soton.ac.uk CALCULATION

3. c.woods@soton.ac.uk CALCULATION

4. c.woods@soton.ac.uk

8. Fire and forget

9. c.woods@soton.ac.uk Fire and forget works for docking Docking simulations can be broken up in this way Each molecule can be docked using a different computer Each molecule is independent from the others We have successfully run docking simulations over a distributed SETI-like screen-saver cluster

10. c.woods@soton.ac.uk Fire and forget is not suitable Lots of chemistry problems cannot be broken down into small independent chunks “Fire and forget” is thus not suitable, and these problems are better solved using dedicated clusters or supercomputers The investigation of protein conformational change represents just such a problem

11. c.woods@soton.ac.uk Protein conformational change The investigation of protein conformational change is important Protein conformational change is important for many biological processes, e.g. signalling pathways One such pathway is used by bacteria to regulate nitrogen metabolism

12. c.woods@soton.ac.uk Protein conformational change N-terminal receiver domain Central catalytic domain DNA binding domain N-terminal receiver domain Central catalytic domain DNA binding domain Nitrogen Regulatory Protein C ( NtrC ) plays a central role in the bacterial metabolism of nitrogen

13. c.woods@soton.ac.uk Asp54 Phosphate NtrB kinase phosphorylates NtrC at aspartate 54 in the receiver domain Protein conformational change Changing nitrogen levels promote the activity of NtrB kinase

14. c.woods@soton.ac.uk Protein conformational change Phosphorylation promotes conformational change in the receiver domain Asp54 Phosphate

15. c.woods@soton.ac.uk Asp54 Phosphate Protein conformational change Phosphorylation promotes conformational change in the receiver domain

16. c.woods@soton.ac.uk Protein conformational change The conformational change causes NtrC to join together to form oligomers These oligomers can bind to DNA and promote the transcription of genes These genes are used to produce proteins that are involved in nitrogen metabolism The signal is passed on because the receiver domain of NtrC changes shape

17. c.woods@soton.ac.uk Investigating conformational change It is difficult to investigate the conformational change experimentally, as P- NtrC is short-lived. Need to simulate the NtrC protein and try to encourage the conformational change on the computer.

18. c.woods@soton.ac.uk

19. MD on the GRID Fire and forget won’t work with MD Each nanosecond of MD needs to be simulated in sequence Can run MD in parallel, but need collection of very similar computers with very good networking Molecular dynamics is not suited to the distributed computing GRID

20. c.woods@soton.ac.uk Adapt the algorithm to the GRID We are developing replica exchange algorithm to use distributed computing and Molecular Dynamics to investigate protein conformational change. The algorithm presents a real challenge to the distributed computing technologies as it is not simple fire and forget.

21. c.woods@soton.ac.uk Replica Exchange Run multiple simulations is parallel Use different conditions in different simulations to enhance conformational change (e.g temperature) 300 K320 K340 K360 K

22. c.woods@soton.ac.uk 300 K 320 K 340 K360 K380 K400 K

23. c.woods@soton.ac.uk 1 300 K 320 K 340 K360 K380 K400 K

24. c.woods@soton.ac.uk 1 300 K 320 K 340 K360 K380 K400 K 1 1111

25. c.woods@soton.ac.uk 2 300 K 320 K 340 K360 K380 K400 K 2 2222

26. c.woods@soton.ac.uk 3 300 K 320 K 340 K360 K380 K400 K 3 3232

27. c.woods@soton.ac.uk 5 300 K 320 K 340 K360 K380 K400 K 4 3234

28. c.woods@soton.ac.uk 5 300 K 320 K 340 K360 K380 K400 K 4 3234 Catch-up cluster

29. c.woods@soton.ac.uk 5 300 K 320 K 340 K360 K380 K400 K 4 4444 Catch-up cluster

30. c.woods@soton.ac.uk Condor Condor project started in 1988 to harness the spare cycles of desktop computers Available as a free download from the University of Wisconsin-Madison Runs on Linux, Unix and Windows. Unix software can be compiled for Windows using Cygwin For more information see http://www.cs.wisc.edu/condor/

31. c.woods@soton.ac.uk

37. Dedicated computing Simulations take a long time compared to dedicated computers Lack of close parallel computing Downtime Competition for resource Lack of motion through temperatures Need condor over parallel nodes

38. c.woods@soton.ac.uk Conclusion Distributed computing is not suited to many chemistry problems We are designing new algorithms to investigate protein conformational change that are better suited to distributed computing We are limited by the inability to run closely parallel jobs

39. c.woods@soton.ac.uk Acknowledgements EPSRC for funding combechem Oz Parchment and David Baker for setting up and running the Condor cluster at Southampton (nearly 1250 nodes and still rising!) Adrian Willey and Rob Gledhill for useful discussions MinDy Visit us at the EPSRC booth! University of Southampton Comb e chem