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Protein structure determination & refinement using QM-derived chemical shifts
- 1. ift her holder KU- ndre ns navn” og dato”: nulinjen, dsæt” > ed / ted og eltet for ”Enhedens Sidefod Department of Chemistry ISTCP8 2013 Dias 1 Quantum Biochemistry: Protein structure determination & refinement using QM- derived chemical shifts Jan H. Jensen, Anders Christensen*, Lars Bratholm, Anders Larsen, Maher Channir, Thomas Hamelryck#, Kresten Lindorff-Larsen#, Kaare Teilum# Departments of Chemistry & Biology# *Novo Nordisk STAR program University of Copenhagen JCTC 2011, 7 2078 & PLoS ONE, submitted (arXiv:1305.2164) Slides can be found at: tinyurl.com/kxch6a7
- 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 Why aren’t more protein structures determined by NMR? Some (over)generalizations: Lack of constraints NMR structures are modeled structures subject to experimental distance-constraints Larger proteins = fewer distance constraints Fewer constraints = less believable structure Department of Chemistry ISTCP8 2013 Dias 2 www.issb.genopole.fr/~faulon/ Proteinstructure.php kpwu.wordpress.com/2011/05/16/statistics- of-nmrx-ray-determined-protein-structures- in-pdb-up-to-may-10-2011/
- 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 Why aren’t chemical shifts used routinely? Some (over)generalizations: It’s complicated Connection between chemicals shifts and structure complicated Empirical chemical shift prediction methods made for different purpose: structural sensitivity & speed issues Fewer distance constraints = sampling problem Pioneering work by D. Baker, Vendruscolo, + others in progress. Baker et al.: use chemical shifts to guide sampling Vendruscolo et al.: use chemical shifts as an energy/force term in MD Department of Chemistry ISTCP8 2013 Dias 3
- 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 The general idea: Department of Chemistry ISTCP8 2013 Dias 4 DOI:10.1021/ar900068s
- 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 Empirical protein chemical shift predictors. Higher accuracy = structural insensitivity Minimize difference between computed and experimental chemical shifts given an x-ray structure. Department of Chemistry ISTCP8 2013 Dias 5 doi:10.1007/s10858-011-9478-4 Proton chemical shifts
- 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 QM says chemical shifts very sensitive to structure. Empirical models disagree Backbone amide proton chemical shifts Department of Chemistry ISTCP8 2013 Dias 6 B3LYP/cc-pVTZ/PCM arXiv:1305.2164 *www.rpi.edu/dept/bcbp/molbiochem/ MBWeb/mb1/part2/protein.htm *
- 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 QM says chemical shifts very sensitive to structure. Empirical models disagree Backbone amide proton chemical shifts: 1ET1 ProCS = QM-based chemical shift predictor Department of Chemistry ISTCP8 2013 Dias 7 B3LYP/cc-pVTZ/PCM arXiv:1305.2164
- 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 ProCS appears less accurate than empirical methods compared to experiment* Backbone amide proton chemical shifts: 1ET1 ProCS = QM-based chemical shift predictor Department of Chemistry ISTCP8 2013 Dias 8 arXiv:1305.2164 *very similar point made by Vila and Scheraga for 13C
- 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 Refining x-ray structure using amide proton chemical shifts and the OPLS force field/GB MCMC ensemble generated using PHAISTOS* + hybrid energy function Ubiquitin (1UBQ), Protein G (1PGB), SMN Tudor Domain (1HMN) Department of Chemistry ISTCP8 2013 Dias 9 arXiv:1305.2164, *DOI:10.1002/jcc.23292 *www.rpi.edu/dept/bcbp/molbiochem/ MBWeb/mb1/part2/protein.htm * 0.31 ppm
- 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 ProCS refinement leads to better H-bond geometries Department of Chemistry ISTCP8 2013 Dias 10 arXiv:1305.2164 ? ?
- 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 QM-derived chemical shifts for remaining nuclei in progress Department of Chemistry ISTCP8 2013 Dias 11 Christensen and Larsen, work in progress Ca 1,000,000 ab initio calculations needed Hα Cα NQM CamShift B3LYP/cc-pVTZ/PCM
- 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 Refining and extended chain (aka protein structure determination) Department of Chemistry ISTCP8 2013 Dias 12 Christensen, Channir work in progress PHAISTOS: CamShift+torus-dbn-cs+isd(NOE)+Profasi 40 million MCMC-iterations/thread
- 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 Summary & outlook Chemical shifts = better (& bigger?) protein structures QM-derived chemical shift prediction needed (and around the corner) Sampling still an issue(?) Chemical shift assignment must be automated and re-addressed for large molecules (Lars Bratholm) Really large proteins = additional constraints needed (CD, SAXS, HD exchange etc) Can QM (PM6-DH+, HF-3c) help in structure refinement? Department of Chemistry ISTCP8 2013 Dias 13
- 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 Thank you! Questions? Slides are available at tinyurl.com/kxch6a7 This talk was brought to you by compchemhighlights.org 5 out of 6 chemists report feeling better after reading CCH* *not intended to be factual statement Department of Chemistry ISTCP8 2013 Dias 14