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The 2013 Bjerrum-Brønsted-Lang Lecture: quantum biochemistry and the rise of semiempirical methods and automation in quantum chemistry

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The 2013 Bjerrum-Brønsted-Lang Lecture: quantum biochemistry and the rise of semiempirical methods and automation in quantum chemistry

  1. 1. ift her holder KU- ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Department of Chemistry 2013 Bjerrum-Brønsted-Lang Lecture Dias 2 Quantum Biochemistry Jan H. Jensen Department of Chemistry University of Copenhagen Slides can be found at: tinyurl.com/bbl2013 June 18, 2013
  2. 2. rter uden stilling punkt- på brug rykning venstre- kst uden stilling, mindsk ng ft her ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Department of Chemistry 2013 Bjerrum-Brønsted-Lang Lecture Dias 3 Computational Chemistry The underlying physical laws necessary for the mathematical theory of a large part of physics and the whole of chemistry are thus completely known, and the difficulty is only that the exact application of these laws leads to equations much too complicated to be soluble. Paul Dirac, 1929 i ∂ ∂t Ψ = ˆHΨ Schrödinger Equation (1926) Not anymore!
  3. 3. rter uden stilling punkt- på brug rykning venstre- kst uden stilling, mindsk ng ft her ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Numerically “exact” solutions: CCSD(T)/CBS Department of Chemistry 2013 Bjerrum-Brønsted-Lang Lecture Dias 4 Bartlett: 10.1103/RevModPhys.79.291
  4. 4. rter uden stilling punkt- på brug rykning venstre- kst uden stilling, mindsk ng ft her ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod CCSD(T)/CBS: benchmarking faster methods CCSD(T)/CBS currently too “slow” for routine chemical applications, but … CCSD(T)/CBS now sufficiently “fast” to generate large amounts of data for benchmarking faster methods Department of Chemistry 2013 Bjerrum-Brønsted-Lang Lecture Dias 5
  5. 5. rter uden stilling punkt- på brug rykning venstre- kst uden stilling, mindsk ng ft her ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod The rise of semi-empirical methods Semi-empirical methods: quantum mechanical (QM) methods with fitted parameters Fitting and validation can now done using CCSD(T)/CBS instead of experimental data: a huge conceptual and practical advance. Better QM: fewer parameters and wider applicability Examples: DFT-D, PM6-DH+, HF-3c HF-3c: HF/minimal basis set corrected for dispersion & BSSE using 9 parameters. No experimental input. Department of Chemistry 2013 Bjerrum-Brønsted-Lang Lecture Dias 6 Grimme: 10.1002/jcc.23317
  6. 6. rter uden stilling punkt- på brug rykning venstre- kst uden stilling, mindsk ng ft her ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Validation against CCSD(T)/CBS: ΔE Department of Chemistry 2013 Bjerrum-Brønsted-Lang Lecture Dias 7 Grimme: 10.1002/jcc.23317 A+B  AB
  7. 7. rter uden stilling punkt- på brug rykning venstre- kst uden stilling, mindsk ng ft her ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Validation against experiment: ΔG Fast methods  frequencies  free energies Department of Chemistry 2013 Bjerrum-Brønsted-Lang Lecture Dias 8 MAD: 2.1 kcal/mol Grimme: 10.1002/chem.201200497
  8. 8. rter uden stilling punkt- på brug rykning venstre- kst uden stilling, mindsk ng ft her ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Semi-empirical methods: new horizons QM structures and free energies for large systems Accurate protein structures Accurate activation free energies for enzymatic reactions Accurate binding free energies for protein-ligand complexes Automation and Computational High-Throughput Screening NMR chemical shift prediction for proteins Screening enzyme mutants Department of Chemistry 2013 Bjerrum-Brønsted-Lang Lecture Dias 9 Grimme: 10.1002/chem.201200497
  9. 9. rter uden stilling punkt- på brug rykning venstre- kst uden stilling, mindsk ng ft her ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod QM structures and free energies for proteins Large systems require different algorithms Department of Chemistry 2013 Bjerrum-Brønsted-Lang Lecture Dias 10 The Effective Fragment Molecular Orbital Method Jan H. Jensen, Anders Christensen and Casper Steinmann (SDU) University of Copenhagen Dmitri Fedorov AIST, Japan JPC A 2010, 114, 8705 PLoS ONE 2012, 7:e41117 PLoS ONE 2012, 7:e44480 PLoS ONE 2013, 8: e60602 arxiv:1305.0676
  10. 10. rter uden stilling punkt- på brug rykning venstre- kst uden stilling, mindsk ng ft her ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Large systems handled by fragmentation Fragmentation  QM calculations  reassembly Department of Chemistry 2013 Bjerrum-Brønsted-Lang Lecture Dias 11
  11. 11. rter uden stilling punkt- på brug rykning venstre- kst uden stilling, mindsk ng ft her ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod All-QM enzymatic reaction barrier Department of Chemistry 2013 Bjerrum-Brønsted-Lang Lecture Dias 12 10.1371/journal.pone.0060602
  12. 12. rter uden stilling punkt- på brug rykning venstre- kst uden stilling, mindsk ng ft her ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Systematic Screening of Enzymatic Reaction Barriers Martin Hediger and Luca De Vico Allan Svendsen (Novozymes) PLoS ONE 2012 7:e49849 PeerJ, submitted (arXiv:1305.6049) arXiv:1209.4469 Automation and High-Throughput Screening Department of Chemistry 2013 Bjerrum-Brønsted-Lang Lecture Dias 13
  13. 13. rter uden stilling punkt- på brug rykning venstre- kst uden stilling, mindsk ng ft her ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Automation and High-Throughput Screening All possible single mutations  PM6 barrier  combination mutants Department of Chemistry 2013 Bjerrum-Brønsted-Lang Lecture Dias 14 ca 500-1000 mutants can be screened
  14. 14. rter uden stilling punkt- på brug rykning venstre- kst uden stilling, mindsk ng ft her ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Automation and High-Throughput Screening Department of Chemistry 2013 Bjerrum-Brønsted-Lang Lecture Dias 15 Proteins Structure Determination from Chemical Shifts Anders Christensen (Novo Nordisk STAR PhD) & Lars Bratholm Thomas Hamelryck, Kresten Lindorff-Larsen, Kaare Teilum (BIO) JCTC 2011, 7 2078 JACS, submitted (arXiv:1305.2164) 10.1021/ar900068s
  15. 15. rter uden stilling punkt- på brug rykning venstre- kst uden stilling, mindsk ng ft her ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod A fast chemical shift predictor for proteins Representative fragments  QM calculations  empirical model QM calculations benchmarked against CCSD(T) Between 500,000 and 1,000,000 QM calculations needed Department of Chemistry 2013 Bjerrum-Brønsted-Lang Lecture Dias 16 arXiv:1305.2164
  16. 16. rter uden stilling punkt- på brug rykning venstre- kst uden stilling, mindsk ng ft her ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Summary CCSD(T)/CBS: Experimental accuracy for small, but now chemically relevant, molecules. CCSD(T)/CBS replaces experiment for parameterization and validation of faster semi-empirical QM methods: more thorough and rigorous parameterization leads to more generally applicable methods. New semi-empirical QM methods are now finally sufficiently accurate to be of practical use. New semi-empirical methods are sufficiently fast for high- throughput screening (1000-1,000,000 QM calculations): new molecular design ideas for experimental chemists. Quantum chemists need to adapt: automation/cheminformatic considerations should be integral part of new modeling projects. Department of Chemistry 2013 Bjerrum-Brønsted-Lang Lecture Dias 17
  17. 17. rter uden stilling punkt- på brug rykning venstre- kst uden stilling, mindsk ng ft her ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Thank you! Questions? Slides are available at tinyurl.com/bbl2013 Department of Chemistry 2013 Bjerrum-Brønsted-Lang Lecture Dias 18
  18. 18. ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod de: og klik på dsæt Department of Chemistry Dias 19 2013 Bjerrum-Brønsted-Lang Lecture

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