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From Transition Metal Chemistry to Molecular Simulation of Proteins

From Transition Metal Chemistry to Molecular Simulation of Proteins. Computational Chemistry Approaches. Adriana Dinescu Wilkes University. Computational Chemistry Applications Structure-Based Drug Design Materials Science Catalysis. Molecular Structures Energy of Molecules

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From Transition Metal Chemistry to Molecular Simulation of Proteins

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  1. From Transition Metal Chemistry to Molecular Simulation of Proteins Computational Chemistry Approaches Adriana Dinescu Wilkes University

  2. Computational Chemistry Applications • Structure-Based Drug Design • Materials Science • Catalysis • Molecular Structures • Energy of Molecules • Many Other Properties • Computational Chemistry Methods • Molecular Mechanics (MM) • Semiempirical Methods (SEQM) • Quantum Mechanics (QM)

  3. Computational Chemistry • Two Major Roles: • Predictive • Explanatory

  4. Preferred Geometry of a Ni(I) Three-Coordinate Complex Eckert, N. A.; Dinescu, A.; Cundari, T. R.; Holland, P. L.Inorg. Chem.2005, 44, 7702.

  5. Preferred Geometry of a Ni(I) Three-Coordinate Complex C2V 2B2 - 7.5 kcal/mol Cs 2A' Y-shape T-shape

  6. Transition State (TS) • TS cannot be captured or directly observed • TS can be determined by searching for first-order saddle points on the potential energy surface (PES) • TS can predict kinetics • Ea = ETS - EReactants TS Reactants • lower Ea higher reaction rate Products

  7. Deprotonation of DTPA DG‡ = 34.82 kcal/mol HA + (H2O)3 A- + H7O3+ Dinescu, A.; Benson, M. T.;J. Phys. Chem., 2008, 112, 12270.

  8. Modeling Studies of Human Glutathione Synthetase (hGS) • ATP-grasp superfamily • Homodimer 474 amino acids each unit Ligands: GSH, ADP, 2 SO42- ions, and 2 Mg2+ ions • 3 loops close the active site G-loop, A-loop, S-loop • Catalyzes the 2nd step of glutathione formation Mg2+ g-glutamylcysteine + glycine + ATP GSH + ADP + Pi

  9. Loop Motion During Catalysis Conformations: yellow – unbound blue – reactant red – product Dinescu, A.; Anderson, M. E.; Cundari, T. R.Biochem. Biophys. Res. Comm. 2007, 353, 450.

  10. Current Research Interests • Bio-inorganic Chemistry • Transition Metal Chemistry • Biological Modeling: Interaction of Collagen with Ions • Carbon Monoxide Dehydrogenase (CODH) • CO + H2O CO2 + 2H+ + 2e-

  11. Employing [Mo-Cu]CODH for Hydrogen Production CO + H2O CO2 + 2H+ + 2e- Proposed reaction mechanism in [Mo-Cu]-CODH enzyme • Cu+1 ? Mo+4 ? Mo+6 ? Dobbek, H.; Gremer, L.; Kiefersauer, R.; Huber, R.; Meyer, O. Proc. Natl. Acad. Sci.2002, 99, 15971.

  12. Redox Active Molybdopterin(MCD) Other non-innocent ligands: Innocent ligand:

  13. Active Site of [Cu-Mo]-CODH Oxidized (active) form Inhibited (BuNC) form

  14. Acknowledgements Jaimee Ash, Rachel Gill, Mike Ryan John Fredericks • Department of Chemistry • Wilkes University • NSF Pittsburgh Supercomputing Center • ACS Petroleum Research Fund

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