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

From Transition Metal Chemistry to Molecular Simulation of Proteins

Computational Chemistry Approaches

Adriana Dinescu

Wilkes University


From transition metal chemistry to molecular simulation of proteins

  • 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)


From transition metal chemistry to molecular simulation of proteins

  • Computational Chemistry

  • Two Major Roles:

  • Predictive

  • Explanatory


From transition metal chemistry to molecular simulation of proteins

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

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

C2V

2B2

- 7.5 kcal/mol

Cs

2A'

Y-shape

T-shape


From transition metal chemistry to molecular simulation of proteins

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


From transition metal chemistry to molecular simulation of proteins

Deprotonation of DTPA

DG‡ = 34.82 kcal/mol

HA + (H2O)3 A- + H7O3+

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


From transition metal chemistry to molecular simulation of proteins

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


From transition metal chemistry to molecular simulation of proteins

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.


From transition metal chemistry to molecular simulation of proteins

  • 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-


From transition metal chemistry to molecular simulation of proteins

  • 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.


From transition metal chemistry to molecular simulation of proteins

Redox Active Molybdopterin(MCD)

Other non-innocent ligands:

Innocent ligand:


From transition metal chemistry to molecular simulation of proteins

Active Site of [Cu-Mo]-CODH

Oxidized (active) form

Inhibited (BuNC) form


From transition metal chemistry to molecular simulation of proteins

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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