Computer simulations using ab initio (density functional theory based) Car-Parinello molecular dynamics (CPMD) and hybrid quantum CPMD / classical MD methodologies are proposed to complement experimental programs at the University of Pennsylvania and elsewhere that focus on enzyme catalysis. The objective of the present proposal is to use state-of-the-art computational methods to explore in detail selected examples of enzymes that exploit the bridged bimetal motif for catalysis. Specifically, mechanistic models of Aeromonas proteolytica aminopeptidase (AAP) and arginase will be examined, as well as the structural and dynamical properties of biomimetic variants. The computational studies will investigate the metal and substrate selectivity of hydrolytic enzymes (AAP), and compare the redox catalase activity of manganese catalase and arginase. In addition, the catalytic mechanism of methane monooxygenase (MMO) will be explored along with modeling the hydrogen peroxide disproportionation and oxygen activation processes at the bimetal core of a biomimetic MMO protein. The long-term goal is to reach a deep understanding of the role of, as well as the fine tuning at, the bridged bimetal motif in redox and hydrolytic enzymatic catalysis. This understanding will be based on a systematic comparative approach to a common motif present in different environments and promoting different reaction processes. The wealth of available experimental data on the bimetal motif lends itself to a controlled study, whose value will be further enhanced by the possibility of suggesting new experiments and ultimately contributing to the design of therapies that target such enzymes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM067689-04
Application #
7161789
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Program Officer
Fabian, Miles
Project Start
2004-01-01
Project End
2008-12-31
Budget Start
2007-01-01
Budget End
2008-12-31
Support Year
4
Fiscal Year
2007
Total Cost
$224,170
Indirect Cost
Name
University of Pennsylvania
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ho, Ming-Hsun; De Vivo, Marco; Dal Peraro, Matteo et al. (2010) Understanding the effect of magnesium ion concentration on the catalytic activity of ribonuclease H through computation: does a third metal binding site modulate endonuclease catalysis? J Am Chem Soc 132:13702-12
Migliore, Agostino (2009) Full-electron calculation of effective electronic couplings and excitation energies of charge transfer states: Application to hole transfer in DNA pi-stacks. J Chem Phys 131:114113
Ho, Ming-Hsun; Klein, Michael L; Kuo, I-F William (2009) Bulk and interfacial aqueous fluoride: an investigation via first principles molecular dynamics. J Phys Chem A 113:2070-4
Vazquez-Mayagoitia, Alvaro; Huertas, Oscar; Brancolini, Giorgia et al. (2009) Ab initio study of the structural, tautomeric, pairing, and electronic properties of seleno-derivatives of thymine. J Phys Chem B 113:14465-72
Migliore, Agostino; Corni, Stefano; Varsano, Daniele et al. (2009) First principles effective electronic couplings for hole transfer in natural and size-expanded DNA. J Phys Chem B 113:9402-15
De Vivo, Marco; Dal Peraro, Matteo; Klein, Michael L (2008) Phosphodiester cleavage in ribonuclease H occurs via an associative two-metal-aided catalytic mechanism. J Am Chem Soc 130:10955-62
Dal Peraro, Matteo; Vila, Alejandro J; Carloni, Paolo et al. (2007) Role of zinc content on the catalytic efficiency of B1 metallo beta-lactamases. J Am Chem Soc 129:2808-16
De Vivo, Marco; Ensing, Bernd; Dal Peraro, Matteo et al. (2007) Proton shuttles and phosphatase activity in soluble epoxide hydrolase. J Am Chem Soc 129:387-94