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Principles of Bioinorganic Chemistry

Principles of Bioinorganic Chemistry.

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Principles of Bioinorganic Chemistry

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  1. Principles of Bioinorganic Chemistry Final papers are due Thursday. The oral presentations will be held in research conference style at MIT's Endicott House estate in Dedham, MA, on Saturday, October 18. Please meet in Kresge parking lot no later than 7:50 AM on Sat. AM. Be sure that Amy has your cell or other phone number.

  2. Protein Tuning of Metal Properties PRINCIPLES: Environment lets similar groups perform different functions Changing number of coordination sites tunes function Redox potential tuned by ligands, H-bonding, substrate Substrate binding affects timing of electron transfer Substrate specificity dictated by active site residue changes Multiple prosthetic groups can couple functions Illustrating the Principles: Methane monooxygenase - inserting ‘O’ into C–H bonds Nitrogenase - Electron transfer and N–N Bond Cleavage Cytochrome c oxidase - O2 to H2O conversion/proton pumping

  3. MMOH Dinuclear Iron Active Site Glu209 Glu243 Glu114 His246 His147 Glu144 Hox, (FeIII)2 Hred, (FeII)2 Both Hox and Hred are charge neutral; X-ray structures by Rosenzweig, Whittington, et al., 1993-present

  4. Reminder

  5. Reminder

  6. Reaction of Hperoxo with Other Substrates Hperoxo reacts with olefins to give epoxides; the ether products decompose in aqueous solution

  7. l 705 or 720 nm l 420 nm Hperoxo and Q Reactions with Ethyl Vinyl Ether Conditions: T = 20 ºC, [H]red = 51.5 mM, [B] = 103 mM Ether concentration in excess and variable, 3 - 70 mM

  8. Results for Hperoxo and Q with Ethyl Vinyl Ether Second Order Rate Constant k = 1500(100) M-1s-1 Second Order Rate Constant k = 223(10) M-1s-1 Rate constant for Hperoxo is significantly greater than for Q. Diethyl ether reacts with Q reacts but Hperoxo does not. Conclusion: Hperoxodoes react with substrates.

  9. Reactions of the Q Intermediate in the sMMO Catalytic Cycle

  10. Reactions of Q with CH4 and C2H6 Reveal Complexities C2H6 CH4 C2D6 CD4 These results imply that, for CH4, H atom abstraction is rate-determining. For C2H6, substrate binding is rate-determining. Brazeau, B. J.; Lipscomb, J. D. Biochemistry2000, 39, 13503-13515. Ambundo, E. A.; Friesner, R. A.; Lippard, S. J. J. Am. Chem. Soc.2002, 124, 8770-8771.

  11. kobs vs Nitromethane Concentration for Q Decay Solid circles, CH3NO2 Open circles CD3NO2 pH = 7, 20 C ; KIE, 8.1 Direct evidence for bound substrate in a Q reaction is facilitated by the high solubility of nitromethane.

  12. Single Turnover of Qwith Nitromethane-d3 at 25°C by Stopped-Flow Infrared Spectroscopy Loss of nitromethane-d3 monitored by stopped-flow IR spectroscopy at 1548 cm-1; kobs 0.39 s-1 Loss of Q monitored by stopped-flow spectrophotometry at 420 nm; kobs 0.39 s-1 First direct monitoring of the hydroxylation of a methane-derived substrate in the sMMOH reaction pathway

  13. KIE for Reactions of Q with CH3X Substratesa Class 1: Binding rate-determining: C2H6, CH3OH Class 2: H atom abstraction rate- determining: CH4, CH3CN, CH3NO2

  14. Mechanism for Methanol Formation E = 0.0 kcal/mol Q Methane

  15. First Electron Transfer for Methanol Formation 17.9 kcal/mol • First electron transfer occurs here and determines the barrier height; one Fe reduced to Fe(III) as O–H bond forms.

  16. Concerted Mechanism for Methanol Formation This transition state is 1.3 kcal/mol uphill from the bound radical intermediate, affording a rate constant in accord with most radical clock substrate probe studies.

  17. Electronic Details of Second Electron Transfer Acceptor Orbital Donor Orbital Bound Methyl Radical (b-Spin) Fe1 d-(x2-y2) (b-Spin-LUMO) ‘Mediator’ Orbital Oxo p(z) (doubly occupied)

  18. Electronic Details of Second Electron Transfer •H–O rotation promotes intramolecular b-electron transfer from the oxo lone pair orbital to the metal-based LUMO. •The remaining radicaloid a-electron on the bridging oxo group has the correct spin to recombine with the b-electron on the substrate to form a s-bond.

  19. Overall Energetics and Methanol Release 1.3 -69.7 E in kcal/mol

  20. QM/MM Summary for Q Hydroxylation of CH3X: Substrate Diffusion Barriers • Substrate diffusion barriers cannot be calculated within the QM/MM framework, but can be inferred from experimental data and QM/MM calculations. • Results for cases where KIE = 1 • Ethane  12.15 kcal/mol; methanol  16.67 kcal/mol • For methane, barrier should be less than ethane, since MMOB tunes the substrate access channel preferentially to methane as a substrate (Lipscomb and co-workers). • For CH3CN, barrier is less than 13.5 kcal/mol. • For CH3NO2, barrier is approximately that of acetonitrile.

  21. Nitrogenase - The P Cluster reduced state oxidized state bridging bridging 6-coord. S

  22. Nitrogenase Fe-Mo Protein

  23. A Catalyst for N2 to NH3 (Schrock)

  24. Cytochrome c Oxidase O2 binds and is reduced at the CuB-heme pair

  25. Proposed O–O Bond Splitting Mechanism O–O bond splitting mechanism in cytochrome oxidase Margareta R. A. Blomberg, Per E. M. Siegbahn, Gerald T. Babcock and Mårten Wikström

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