1. Computational Chemistry Robots ACS Sep 2005 Computational Chemistry Robots ACS Sep 2005 Computational Chemistry Robots J. A. Townsend, P. Murray-Rust, S. M. Tyrrell, Y. Zhang jat45@cam.ac.uk

2. Computational Chemistry Robots ACS Sep 2005 Can high-throughput computation provide a reliable “experimental” resource for molecular properties? Can protocols be automated? Can we believe the results?

3. Computational Chemistry Robots ACS Sep 2005 Aspects of complete automation Humans must validate protocols rather than individual data Low rates of error must be addressed Users should know the rates of error and degree of conformance

4. Computational Chemistry Robots ACS Sep 2005 Approaches to conformance Explore limits of job behaviour (times, convergence, etc.) Analyse reproducibility Vary and analyse effects of parameters and algorithms Compare output with other “measurements” of same quantity

5. Computational Chemistry Robots ACS Sep 2005 The overall view moleculescomputationdissemination

6. Computational Chemistry Robots ACS Sep 2005 The overall view moleculescomputationdissemination Check results

7. Computational Chemistry Robots ACS Sep 2005 Components of System Workflow for management of jobs (Taverna) Natural Language Processing based parsing of outputs (JUMBOMarker) Pairwise comparison of data sets (R) Analysis of mean and variance Detection and analysis of outliers

8. Computational Chemistry Robots ACS Sep 2005 Computing the NCI database MOPAC PM5 a a MOPAC PM5 – collaboration with J.J.P. Stewart

9. Computational Chemistry Robots ACS Sep 2005 Protocol Log Files Parse System Crashes Science Errors Analysis Pathological Behaviour Statistics Other Science Disseminate Results Unsuitable Data Program Crashes Inform Developer

10. Computational Chemistry Robots ACS Sep 2005 Taverna Workflow programs allow a series of small tasks to be linked together to develop more complex tasks Open Source myGRID, eScience European Bioinformatics Institute University of Manchester

11. Computational Chemistry Robots ACS Sep 2005 An Example Taverna Workflow

12. Computational Chemistry Robots ACS Sep 2005 Parsing Log Files to CML Coordinates Molecular Formula Calculation Type Point Group Dipole Total Energy Computational Chemistry Log Files

13. Computational Chemistry Robots ACS Sep 2005 CompChem Output Coordinates Energy Levels Vibrations Coordinates Energy Level Vibration CML File CMLCore CMLComp CMLSpect Input/jobControlGeneral Parsers

14. Computational Chemistry Robots ACS Sep 2005 Dissemination of results LOG FILECML FILEHUMAN DISPLAY WWMM* Server and DSpace Outside world JUMBOMarker NLP-based log file parser * World Wide Molecular Matrix

15. Computational Chemistry Robots ACS Sep 2005 InChI: IUPAC International Chemical Identifier A non-proprietary unique identifier for the representation of chemical structures. A normal, canonicalised and serialised form of a chemical connection table. InChI FAQ: http://wwmm.ch.cam.ac.uk/inchifaq/

16. Computational Chemistry Robots ACS Sep 2005 Proteus molecules * Calculation JUNK Cured by MOPAC * Proteus was a shape changing ocean deity

17. Computational Chemistry Robots ACS Sep 2005 Proteus molecules Calculation Input JUNK

18. Computational Chemistry Robots ACS Sep 2005 How do we know our results are valid? Computational Method 1 Computational Method 2 Experiment

19. Computational Chemistry Robots ACS Sep 2005 J.J.P. Stewart’s example Calculated  H f – Expt  H f

20. Computational Chemistry Robots ACS Sep 2005 GAMESS MOPAC results GAMESS a 631G* B3LYP Log Files a Project with Kim Baldridge and Wibke Sudholt

21. Computational Chemistry Robots ACS Sep 2005 Protocol Log Files Parse System Crashes Science Errors Analysis Pathological Behaviour Statistics Other Science Disseminate Results Unsuitable Data Program Crashes Inform Developer

22. Computational Chemistry Robots ACS Sep 2005 Repeat runs, different methods Multiple runs give same final structure from same input Changing memory allocation doesn’t make a difference

23. Computational Chemistry Robots ACS Sep 2005 Pathological behaviour - Early detection 100 min631G*, B3LYP200 min 15 min 631G*, B3LYP 10080 min divinyl ether trans-Crotonaldehyde Z matrix

24. Computational Chemistry Robots ACS Sep 2005 Times to run jobs

25. Computational Chemistry Robots ACS Sep 2005 Analysis of different computational methods Mean - Overall difference Normality - Distribution of values Outliers - Unusual molecules? Variance - Spread of the data, depends on both distributions. (standard deviation)

26. Computational Chemistry Robots ACS Sep 2005 Probability Plot (Normal QQ plot)

27. Computational Chemistry Robots ACS Sep 2005 Mean of distribution (Approx - 0.03 Å) Range over which sample distribution is approximately normal Outliers Probability Plot (Normal QQ plot) S.D. 0.020 Å

28. Computational Chemistry Robots ACS Sep 2005 All bonds*  r (MOPAC – GAMESS) / Å * Excludes bonds to Hydrogenc

29. Computational Chemistry Robots ACS Sep 2005 All bonds*  r (MOPAC – GAMESS) / Å Good agreement Nearly normal Outliers S.D. 0.005 Å * Excludes bonds to Hydrogenc

30. Computational Chemistry Robots ACS Sep 2005 2- Bad molecules and data usually cause outliers Na P O O H H

31. Computational Chemistry Robots ACS Sep 2005 Mean  r (M - G) / Å Standard Error of the Mean / Å CNOFSCl C -0.0060.020-0.010-0.014-0.040-0.037 0.000 0.001 N 0.006-0.037 -0.055 0.001 0.009 O -0.087 -0.070 0.004 0.014 All values given to 3 significant figures

32. Computational Chemistry Robots ACS Sep 2005  r CC bonds (M - G) / Å

33. Computational Chemistry Robots ACS Sep 2005  r CC bonds (M - G) / Å Good agreement Nearly normalOutliers S.D. 0.013 Å JUNK

34. Computational Chemistry Robots ACS Sep 2005 Selection of molecules with C C  r (M - G) > 0.05 Angstroms

35. Computational Chemistry Robots ACS Sep 2005 Y = 0.0277 X – 0.0061 Non aromatic C C bonds adjacent to CF n

36. Computational Chemistry Robots ACS Sep 2005  r NN bonds (M - G) / Å

37. Computational Chemistry Robots ACS Sep 2005 Good agreement Nearly normal Kink S.D. 0.022 Å  r NN bonds (M - G) / Å

38. Computational Chemistry Robots ACS Sep 2005 Density plot of  r NN bonds (M - G) / Å

39. Computational Chemistry Robots ACS Sep 2005 LEFT RIGHT Density plot of  r NN bonds (M - G) / Å

40. Computational Chemistry Robots ACS Sep 2005 Most common fragments found in Left set but not Right set C(sp 3 ) (sp 3 ) S(sp 2 ) N(ar) C(sp 2 ) S(sp 2 ) N(ar) C(sp 2 ) Or

41. Computational Chemistry Robots ACS Sep 2005 GAMESS Log Files Comparison of theory and experiment CIF* CIF 2 CML * CIF: Crystallographic Information File

42. Computational Chemistry Robots ACS Sep 2005 Reading Acta Crystallographica Section E

43. Computational Chemistry Robots ACS Sep 2005 All bonds*  r (Cryst. – GAMESS) /Å Single molecules, no disorder * Excludes bonds to Hydrogenc

44. Computational Chemistry Robots ACS Sep 2005 All bonds*  r (Cryst. – GAMESS) /Å Single molecules, no disorder Mean  r - 0.011 Å Nearly normal Outliers S.D. 0.014 Å * Excludes bonds to Hydrogenc

45. Computational Chemistry Robots ACS Sep 2005  r CC bonds (C – G) /Å

46. Computational Chemistry Robots ACS Sep 2005 Mean  r - 0.01 Å Nearly normal S.D. 0.009 Å  r CC bonds (C – G) /Å

47. Computational Chemistry Robots ACS Sep 2005  r CO bonds (C – G) /Å

48. Computational Chemistry Robots ACS Sep 2005 Good agreement Nearly normal Outliers ? S.D. 0.011 Å  r CO bonds (C – G) /Å

49. Computational Chemistry Robots ACS Sep 2005  r = +0.08 Å Chemistry can cause outliers H movement

50. Computational Chemistry Robots ACS Sep 2005 Conclusions Protocols can be automated Machines can highlight unusual behaviour, geometries and distribution of results for humans to consider Computational programs can provide high quality “experimental” molecular properties

51. Computational Chemistry Robots ACS Sep 2005 Thanks J.J.P. Stewart Kim Baldridge Wibke Sudholt Simon Tyrrell Yong Zhang Peter Murray-Rust Unilever

52. Computational Chemistry Robots ACS Sep 2005 Questions Homepage: http://wwmm.ch.cam.ac.uk InChI FAQ: http://wwmm.ch.cam.ac.uk/inchifaq R: http:// www.r-project.org Taverna: http://taverna.sourceforge.net/ MOPAC 2002: http://www.cachesoftware.com/mopac/ GAMESS: http:// www.msg.ameslab.gov/GAMESS/GAMESS.html