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Quantum Biochemistry: the rise of semiempirical methods
- 1. Department of Chemistry ift her holder KU- ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Quantum Biochemistry Jan H. Jensen Department of Chemistry University of Copenhagen Slides can be found at: DOI:10.6084/m9.figshare.912548 Dias 1
- 2. ft her Department of Chemistry Computational Chemistry Schrödinger Equation (1926) rter uden stilling ∂ ˆ i Ψ = H Ψ ∂t punktpå brug rykning venstrekst uden stilling, mindsk ng ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod 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 Dias 2 Not anymore!
- 3. ft her Department of Chemistry Numerically “exact” solutions: CCSD(T)/CBS rter uden stilling punktpå brug rykning venstrekst uden stilling, mindsk ng ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Dias 3 Bartlett: 10.1103/RevModPhys.79.291
- 4. Department of Chemistry ft her CCSD(T)/CBS: benchmarking faster methods rter uden stilling CCSD(T)/CBS currently too “slow” for routine chemical applications, but … punktpå brug rykning CCSD(T)/CBS now sufficiently “fast” to generate large amounts of data for benchmarking faster methods venstrekst uden stilling, mindsk ng ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Dias 4
- 5. Department of Chemistry ft her The rise of semi-empirical methods rter uden stilling Semi-empirical methods: quantum mechanical (QM) methods with fitted parameters punktpå brug rykning venstrekst uden stilling, mindsk ng ndre ns navn” og dato”: 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. nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Grimme: 10.1002/jcc.23317 Dias 5
- 6. ft her Department of Chemistry Validation against CCSD(T)/CBS: ΔE rter uden stilling punktpå brug rykning venstrekst uden stilling, mindsk ng ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod A+B è AŸB Dias 6 Grimme: 10.1002/jcc.23317
- 7. ft her rter uden stilling Department of Chemistry Validation against experiment: ΔG Fast methods è frequencies è free energies punktpå brug rykning venstrekst uden stilling, mindsk ng ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod MAD: 2.1 kcal/mol Dias 7 Grimme: 10.1002/chem.201200497
- 8. ft her rter uden stilling punktpå brug rykning venstrekst uden stilling, mindsk ng Department of Chemistry 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 ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Dias 8 Grimme: 10.1002/chem.201200497
- 9. ft her Department of Chemistry QM structures and free energies for proteins Large systems require different algorithms rter uden stilling The Effective Fragment Molecular Orbital Method punktpå brug rykning Jan H. Jensen, Anders Christensen and Casper Steinmann (SDU) University of Copenhagen venstrekst uden stilling, mindsk ng Dmitri Fedorov AIST, Japan JPC A 2010, 114, 8705 PLoS ONE 2012, 7:e41117 PLoS ONE 2012, 7:e44480 PLoS ONE 2013, 8: e60602 PLoS ONE 2014 (arxiv:1305.0676) ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Dias 9
- 10. ft her rter uden stilling Department of Chemistry Large systems handled by fragmentation Fragmentation è QM calculations è reassembly punktpå brug rykning venstrekst uden stilling, mindsk ng ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Dias 10
- 11. ft her Department of Chemistry All-QM enzymatic reaction barrier rter uden stilling punktpå brug rykning venstrekst uden stilling, mindsk ng ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Dias 11 10.1371/journal.pone.0060602
- 12. ft her rter uden stilling Department of Chemistry Automation and High-Throughput Screening Systematic Screening of Enzymatic Reaction Barriers Martin Hediger and Luca De Vico punktpå brug rykning Allan Svendsen (Novozymes) PLoS ONE 2012 7:e49849 PeerJ 2013 1:e111 PeerJ 2013 1:e145 venstrekst uden stilling, mindsk ng ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Dias 12
- 13. Department of Chemistry ft her Automation and High-Throughput Screening rter uden stilling All possible single mutations è PM6 barrier è combination mutants punktpå brug rykning venstrekst uden stilling, mindsk ng ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod ca 500-1000 mutants can be screened Dias 13
- 14. ft her rter uden stilling punktpå brug rykning Department of Chemistry Automation and High-Throughput Screening 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 PLoS ONE 2013, 8:e84123 venstrekst uden stilling, mindsk ng ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Dias 14 10.1021/ar900068s
- 15. Department of Chemistry ft her A fast chemical shift predictor for proteins rter uden stilling Representative fragments è QM calculations è empirical model punktpå brug rykning venstrekst uden stilling, mindsk ng QM calculations benchmarked against CCSD(T) Between 500,000 and 1,000,000 QM calculations needed ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Dias 15 PLoS ONE 2013, 8:e84123
- 16. Department of Chemistry ft her Summary rter uden stilling CCSD(T)/CBS: Experimental accuracy for small, but now chemically relevant, molecules. punktpå brug rykning venstrekst uden stilling, mindsk ng ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod 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 highthroughput 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. Dias 16
- 17. Department of Chemistry ft her Thank you! Questions? rter uden stilling Slides are available at DOI:10.6084/m9.figshare.912548 punktpå brug rykning venstrekst uden stilling, mindsk ng ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Dias 17
- 18. Department of Chemistry de: og klik på dsæt ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Dias 18