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Computing and Chemistry

Computing and Chemistry. david.wishart@ualberta.ca 3-41 Athabasca Hall Sept. 16, 2013. How Do We Know?. Benzene. Sucrose. How Do We Know?. Hemoglobin. Powers of 10. http://micro.magnet.fsu.edu/primer/java/scienceopticsu/powersof10/. Powers of 10.

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Computing and Chemistry

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  1. Computing and Chemistry david.wishart@ualberta.ca 3-41 Athabasca Hall Sept. 16, 2013

  2. How Do We Know? Benzene Sucrose

  3. How Do We Know? Hemoglobin

  4. Powers of 10 http://micro.magnet.fsu.edu/primer/java/scienceopticsu/powersof10/

  5. Powers of 10 http://micro.magnet.fsu.edu/primer/java/scienceopticsu/powersof10/

  6. Powers of 10 http://micro.magnet.fsu.edu/primer/java/scienceopticsu/powersof10/

  7. Powers of 10 http://micro.magnet.fsu.edu/primer/java/scienceopticsu/powersof10/

  8. Powers of 10 http://micro.magnet.fsu.edu/primer/java/scienceopticsu/powersof10/

  9. Powers of 10 http://micro.magnet.fsu.edu/primer/java/scienceopticsu/powersof10/

  10. Powers of 10 http://micro.magnet.fsu.edu/primer/java/scienceopticsu/powersof10/

  11. Powers of 10 http://micro.magnet.fsu.edu/primer/java/scienceopticsu/powersof10/

  12. Powers of 10 http://micro.magnet.fsu.edu/primer/java/scienceopticsu/powersof10/

  13. Powers of 10 http://micro.magnet.fsu.edu/primer/java/scienceopticsu/powersof10/

  14. Powers of 10 http://micro.magnet.fsu.edu/primer/java/scienceopticsu/powersof10/

  15. Powers of 10 http://micro.magnet.fsu.edu/primer/java/scienceopticsu/powersof10/

  16. Our Seeing Limits (and Limitations) Free $5 $5000 $500,000 1 m 1 x 10-3 m 1x10-6 m 1x10-9 m Live, moving Live, moving Fixed, stained Fixed, stained

  17. Our Seeing Limits (and Limitations) $5,000,000 $500,000,000 1x10-10 m 1x10-12 m Extracted, crystallized Atomized, vaporized

  18. Seeing Molecules • Can’t use visible light • Can’t use electrons (EM) • Have to use X-ray scattering • Have to use Nuclear Magnetic Resonance (NMR) spectroscopy • Have to use mass spectrometry • All require computers & computing

  19. X-ray Crystallography

  20. Crystallization A Crystal

  21. Crystallization Hanging Drop Experiment for Cyrstallization

  22. Diffraction Apparatus

  23. A Bigger Diffraction Apparatus Synchrotron Light Source

  24. Diffraction Principles*** nl = 2dsinq

  25. Diffraction Principles Corresponding Diffraction Pattern A string of atoms

  26. Converting Diffraction Data to Electron Density F T

  27. Fourier Transformation i(xyz)(hkl) F(x,y,z) = f(hkl)e d(hkl) Converts from units of inverse space to cartesian coordinates

  28. Resolution 1.2 Å 2 Å 3 Å Resolution describes the ability of an imaging system to resolve detail in the object that is being imaged.

  29. Electron Density Tracing

  30. Crystallography (Then & Now) 2010 1959

  31. Crystallography (Then & Now) 1953 2010

  32. X-ray Crystallography • Key is to measure both phase and amplitude of X-rays (unfortunately we can’t measure phase) • Trick is to guess phase, use a crutch (anomalous dispersion) or calculate the phase using pattern recognition (direct method) • Direct method (purely computational) works for small molecules (<1000 atoms) but not for large • Anyone who solves the “direct phasing problem” for all molecule sizes wins the Nobel Prize

  33. Computational Challenges in X-ray Crystallography • Solving the direct phase problem • Algorithmics, Parallelism • Developing robotic crystallography stations (doing what humans do) • Robotics • Predicting and planning optimal crystallization conditions • Machine learning, Neural Nets • Automated electron density tracing • AI, Machine learning

  34. 2 Main Methods to Solve Structures in Chemistry X-ray NMR

  35. NMR Spectroscopy Radio Wave Transceiver

  36. Principles of NMR • Measures nuclear magnetism or changes in nuclear magnetism in a molecule • NMR spectroscopy measures the absorption of light (radio waves) due to changes in nuclear spin orientation • NMR only occurs when a sample is in a strong magnetic field • Different nuclei absorb at different energies (frequencies)

  37. Principles of NMR

  38. FT NMR Free Induction Decay FT NMR spectrum

  39. Signal Processing

  40. Fourier Transformation iwt F(w) = f(t)e dt Converts from units of time to units of frequency

  41. 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 1H NMR Spectra Exhibit… • Chemical Shifts (peaks at different frequencies or ppm values) • Splitting Patterns (from spin coupling) • Different Peak Intensities (# 1H)

  42. NMR Spectra Small Molecule Big Molecule 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

  43. Simplifying Complex Spectra

  44. Multidimensional NMR 1D 2D 3D MW ~ 500 MW ~ 10,000 MW ~ 30,000

  45. The NMR Challenge • Peak positions tell you atom types • Peak clusters tells about atom type proximity or neighborhood • Peak intensities tell you how many atoms • How to interpret peak intensities, peak clusters and peak positions to generate a self-consistent structure?

  46. Solving a Crossword Puzzle • Dictionary of words and definitions (or your brain) • Match word length • Match overlapping or crossing words • All words have to be consistent with geometry of puzzle

  47. NMR Spectroscopy (The Old Way) Peak Positions Peak Height J-Couplings

  48. NMR Spectroscopy (The New Way) Peak Positions Peak Height J-Couplings Computer Aided Structure Elucidation

  49. Computer-Aided Structure Elucidation

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