From transition metal chemistry to molecular simulation of proteins
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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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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

  • Many Other Properties

  • Computational Chemistry Methods

  • Molecular Mechanics (MM)

  • Semiempirical Methods (SEQM)

  • Quantum Mechanics (QM)


  • Computational Chemistry

  • Two Major Roles:

  • Predictive

  • Explanatory


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.


Preferred Geometry of a Ni(I) Three-Coordinate Complex

C2V

2B2

- 7.5 kcal/mol

Cs

2A'

Y-shape

T-shape


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


Deprotonation of DTPA

DG‡ = 34.82 kcal/mol

HA + (H2O)3 A- + H7O3+

Dinescu, A.; Benson, M. T.;J. Phys. Chem., 2008, 112, 12270.


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


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.


  • 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-


  • 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.


Redox Active Molybdopterin(MCD)

Other non-innocent ligands:

Innocent ligand:


Active Site of [Cu-Mo]-CODH

Oxidized (active) form

Inhibited (BuNC) form


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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