(gc3551)Complex Enzymatic Reactions Studied by Molecular Modeling and Electronic Structure Calculations.
EMSL Project ID
3551
Abstract
This proposal concerns the continued development and application of modeling capabilities for the study of complex enzymatic reactions, in particular those that involve electron transfer and/or proton transfer steps. Elucidation of the molecular-level processes, including long-range electron and proton transfer steps, and long-time conformational protein dynamics requires extending computational tools and techniques beyond what is currently available. This project will, therefore, also provide the tools that enable the modeling and simulation of increasingly complex systems with a reduced level of approximation, an increased level of model sophistication, and an increased level of accuracy than achieved heretofore. This goal will be achieved through extension and development of new capabilities of NWChem, our massively parallel computational chemistry software suite for electronic structure and classical molecular dynamics simulations.The group at PNNL will focus on the electron transfer and proton hopping processes of the reaction mechanism in the respiratory cycle of iron-reducing bacteria. Computational resources are requested to support a DOE funded computational project aimed at providing and applying the computational tools required for a detailed molecular-level characterization and understanding of the enzymatic reactivity of these bacteria through modeling and simulation. One of the target enzymatic systems in this work is, therefore, the soluble flavocytochrome c3 fumarate reductase of Shewanella frigidimarina, as a complementary component of other ongoing research efforts at PNNL aimed at the detailed understanding of microbe-mediated metal reduction processes in the subsurface. This work is critical to the advance of potential bioremediation technologies for contaminated lands.
Another target system in this work will be cytochrome c oxidase from Paracoccus denitrificans. The Frankfurt group determined the atomistic structure of this enzyme in 1995 by X-ray crystallography and made major contributions towards characterizing the proton transfer and proton pumping steps by site-directed mutagenesis, spectroscopy, and electrophysiology. Here, the complex coupling of several electron and proton transfer steps will be elucidated in atomic and electronic detail in a close collaboration between theory and experiment. The Saarbr?cken group developed the Q-HOP molecular dynamics simulation methodology that includes stochastic proton hopping events. Hopping probabilites between typical biochemical donor-acceptor systems are pre-calculated and parameterized against quantum-mechanical calculations. The method is ideally suited for studying complex dynamical proton transfer situations in large biomolecular systems. Applications of the method include the proton shuttle between chromophore and surrounding amino acids in green fluorescent protein, and proton diffusion through aquaporin. The Frankfurt and Saarbr?cken groups tightly colloborate on applying the Q-HOP methodology to cytochrome c oxidase.
The Louisville group is developing a computational modeling framework that will facilitate simulation of resonance Raman spectra of active site chromophores residing in complex biological matrices with the intent of providing a reliable interpretational framework for frequencies and intensities in terms of key structural elements of the chromophore and its immediate environment. The objective of this effort is the development of the methodology that will allow determination of a vibrational force field for hemes residing within the protein active site, calculation of excited states of hemes using time-dependent density functional theory to provide a solid foundation in modeling resonance Raman intensities for comparison with available data, and development of a user-friendly normal coordinate analysis program that will link frequency and Raman intensity calculations.
The Arizona group will model the interactions of protein-bound hemes with small molecules such as CO, NO and O2 in order to elucidate the correlation between heme structural changes and spectral characteristics observed in vibrational and M?ssbauer spectra. This will require some re-parametrization of existing DFT functionals for the description of hemes using the QM/MM method as it is implemented in NWChem, which will allow the Arizona group to elucidate the electronic, electrostatic and structural influences of small-molecule binding in heme proteins.
Project Details
Project type
Capability Research
Start Date
2003-09-30
End Date
2006-10-01
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
Gu, W., Frigato, T., Straatsma, T.P., and Helms, V. (2007) Angewandte Chemie, Dynamic Protonation Equilibrium of Solvated Acetic Acid, Vol. 119, p. 2997-3001 (English version).
Herzog E, T Frigato, V Helms, and CD Lancaster . 2006. "Energy barriers of proton transfer reactions between amino acid side chain analogs and water from ab initio calculations ." Journal of Computational Chemistry 27(13):1534-1547.
Olkhova E, VH Helms, and H Michel. 2005. "Titration Behavior of Residues at the Entrance of the D-Pathway of Cytochrome c Oxidase from Paracoccus denitrificans Investigated by Continuum Electrostatic Calculations." Biophysical Journal 89(4):2324-2331.
Rosso KM, D Smith, and M Dupuis. 2004. "Aspects of aqueous iron and manganese (II/III) self-exchange electron transfer reactions." Journal of Physical Chemistry A 108(24):5242-5248.
Smith D, M Dupuis, ER Vorpagel, and T Straatsma. 2003. "Characterization of Electronic Structure and Properties of a bis(histidine) Heme Model Complex." Journal of the American Chemical Society 125(9):2711-2717.
Smith DM, KM Rosso, M Dupuis, M Valiev, and T Straatsma. 2006. "Electronic Coupling between Heme Electron-Transfer Centers and Its Decay with Distance Depends Strongly on Relative Orientation." Journal of Physical Chemistry B 110(31):15582-15588.
Smith DM, M Dupuis, and T Straatsma. 2005. " Multiplet splittings and other properties from Density Functional Theory: An assessment in iron-porphyrin systems." Molecular Physics 103(2-3):273-278.
Straatsma T. 2005. "Scalable Molecular Dynamics." Journal of Physics: Conference Series 16:287-299.