Rajeev Prabhakar

Ph.D., Stockholm University, Stockholm, Sweden, 2003
Postdoctorate, Emory University, Atlanta, GA, 2003-06

E-mail: rpr@miami.edu

Research in a Nugget

Brief description of research

Publications 2004-Present

Link to our laboratory website: Prabhakar Group


Research in a Nugget


Brief description of research

Investigation of Enzymatic and Non-enzymatic Reaction Mechanisms
Computational chemistry is a fast emerging field and today is widely applied to solve complex chemical and biochemical problems in both academia and the chemical and pharmaceutical industries. In this field, highly accurate quantum chemical methods implemented in the advanced commercial software and state-of-the-art computers including supercomputing facilities are used to explore chemistry. In our research group, we apply computational approaches, namely pure quantum mechanical (QM), hybrid quantum mechanics/ molecular mechanics (QM/MM) and molecular simulations, to investigate reaction mechanisms catalyzed by both enzymatic and non-enzymatic systems.

Computational study of Alzheimer's disease
Beta-amyloidosis and oxidative stress have been implicated as root causes of Alzheimer’s disease (AD). Beta-amyloidosis could be described as the generation and extracellular aggregation of 40-42 amino acid residues containing amyloid beta (Aß) peptides to form senile plaques. The Aß42 peptide has been observed to be a major component of these plaques. According to a widely accepted theory concerning the role of these peptides in AD known as the oxidative stress mechanism, the aggregated Aß peptide, in concert with oxidants and bound metal ions (Cu(II), Zn(II) and Fe(III)), initiates free radical processes resulting in the formation of reactive oxygen species (ROS) such as hydrogen peroxide, superoxide and hydroxyl radicals, which eventually leads to neuronal death. 
The current potential therapeutic strategies for AD include blocking the generation and aggregation of Aß peptides, inhibiting the cytotoxic effects, and disrupting of preformed fibrils. However, our efforts in this direction are hindered by the lack of atomic level understanding of biochemical processes occurring in AD. Due to inherent complexities (absence of x-ray structures, fast rate of aggregation, insolubility of aggregates, short life-time and intricate electronic structure of intermediates, etc.) this understanding can’t be achieved by experiments alone and requires multidisciplinary scientific approaches. We propose a radically different approach to this problem through the development and application of a comprehensive theoretical and computational strategy involving molecular dynamics (MD), quantum mechanics (QM), hybrid quantum mechanics/molecular mechanics (QM/MM), bioinformatics and spectroscopy techniques to investigate complex chemical and physical processes in beta-amyloidosis and the oxidative stress mechanism. In particular, we aim to study generation, degradation, and prevention of the aggregation of Aß-peptides, and disruption of preformed Aß-fibrils. The outcome of our studies will provide an atomic level understanding of biochemical processes occurring in AD and their outcome will advance our efforts to develop effective therapeutic strategies for this disease.


Publications 2004-Present

2010

Oxygen Binding to [Pd(L)(L0)] (L= NHC, L0 = NHC or PR3, NHC = N-Heterocyclic Carbene). Synthesis and Structure of a Paramagnetic trans-[Pd(NHC)2(η1-O2)2] Complex
Xiaochen Cai, Subhojit Majumdar, George C. Fortman, Catherine S. J. Cazin, Alexandra M. Z. Slawin, Charles Lhermitte, Rajeev Prabhakar, Meaghan E. Germain, Taryn Palluccio, Steven P. Nolan, Elena V. Rybak-Akimova, Manuel Temprado, Burjor Captain, and Carl D. Hoff The Journal of the American Chemical Society2010, in press.  

Restricted rotation due to lack of free space within a capsule translates into product selectivity:  Photochemistry of cyclohexyl phenyl ketones within a water-soluble organic capsule
Revathy Kulasekharan, Rajib Choudhury, Rajeev Prabhakar and V. RamamurthyChemComm2010, in press.

Which One Among Aspartyl Protease, Metallopeptidase, and Artificial Metallopeptidase is the Most Efficient Catalyst in Peptide Hydrolysis? 
R Bora, A Barman, X Zhu, M Ozbil, R Prabhakar Journal of Physical Chemistry B2010,114,10860–10875.

A closed nano-container enables thioketones to phosphoresce at room temperature in aqueous solution
Nithyanandhan Jayaraj, V.S.N. Maddipatla, Rajeev Prabhakar, Steffen Jockusch, N.J. Turo and V. Ramamurthy
Journal of Physical Chemistry B2010114, 14320–14328.

Elucidation of interactions of Alzheimer Amyloid b-peptides (Ab40 and Ab42) with Insulin Degrading Enzyme (IDE): A molecular dynamics study. Ram Prasad Bora and Rajeev Prabhakar. Biochemistry2010, 49 ,3947–3956.

Elucidation of Insulin Degrading Enzyme Catalyzed Site Specific Hydrolytic Cleavage of Amyloid β-Peptide: A Comparative DFT Study. R. Bora, M. Ozbil, R. Prabhakar Journal of Biological Inorganic Chemistry2010,15 ,485-495.

Theoretical Insights into the Mechanism of Selective Peptide Bond Hydrolysis Catalyzed by [Pd(H2O)4]2+. A. Kumar, X. Zhu, K. Walsh, R. Prabhakar Inorganic Chemistry2010, 49, 38-46.

2009

Translational, rotational and internal dynamics of amyloid beta-peptides (Abeta40 and Abeta42) from molecular dynamics simulations. R. Bora, R. Prabhakar J. Chem. Phys., 2009, 131, 155103-155103. 
[selected for online publication in the Virtual Journal of Nanoscale Science and Technology, Nov. 2, 2009]

Computational Insights into Aspartyl Protease Activity of Presenilin 1 (PS1) Generating Alzheimer Amyloid β-Peptides (Aβ40 and Aβ42). R. Singh, A., Barman, and Rajeev Prabhakar Journal of Physical Chemistry B 2009, 113, 2990-2999.

Computational Insights in the Development of Novel Therapeutic Strategies for Alzheimer’s Disease (AD). Rajeev Prabhakar Future Medicinal Chemistry2009, 1(1),119-135.

Insights into the Mechanism of Methionine Oxidation Catalyzed by Metal (Cu2+, Zn2+ and Fe3+) - Amyloid Beta (Aβ) Peptide Complexes: A Computational Study. A. Barman, W. Taves, and Rajeev Prabhakar, Journal of Computational Chemistry2009, 30(9), 1405-1413.

Modeling the self-assembly dynamics of macromolecular protein aggregates underlying neurodegenerative disorders. Z. Zhao, R. Singh, A. Barman, N. F. Johnson, and Rajeev Prabhakar Computational and Theoretical Nanoscience 2009, 6(6),1338-1351(14)

Crystallographic, Spectroscopic, and Computational Analysis of a Flavin-C4a-Oxygen Adduct in Choline Oxidase. A. M. Orville, G. T. Lountos, S. Finnegan, G. Gadda, and Rajeev Prabhakar. Biochemistry 2009, 48, 720-728

Coordination-Mode Control of Bound Nitrile Radical Complex Reactivity: Intercepting End-on Nitrile-Mo(III) Radicals at Low Temperature. M. Germain, M. Temprado, A.  Castonquay, O. Kraytova, E. Rybak-Akimova, Elena, J. Curley, A. Mendiratta, Y-C. Tsai, C. Cummins, Rajeev Prabhakar, J. McDonough and C. HoffJournal of American Chemical Society 2009, 131 (42), 15412–15423

2008 
Crystallographic, Spectroscopic, and Computational Analysis of a Flavin-C4a-Oxygen Adduct in Choline Oxidase. A. M. Orville, G.  T. Lountos, S. Finnegan, G. Gadda, and Rajeev Prabhakar Biochemistry 2008, in press.

Insights into the Mechanism of Methionine Oxidation Catalyzed by Metal (Cu2+, Zn2+ and Fe3+) - Amyloid Beta (Aß) Peptide Complexes: A Computational Study.
A. Barman, W. Taves, and Rajeev Prabhakar, Journal of Computational Chemistry2008, Published (online).

Modeling the self-assembly dynamics of macromolecular protein aggregates underlying neurodegenerative disorders. 
Z. Zhao, R. Singh, A. Barman, N. F. Johnson, and Rajeev Prabhakar Computational and Theoretical Nanoscience 2008, in press.

Comparative Molecular Dynamics Studies of Wild-Type and oxidized forms of Full-Length Alzheimer Amyloid ß-Peptides Aß(1-40) and Aß(1-42). 
L. Triguero, R. Singh and Rajeev Prabhakar Journal of Physical Chemistry B 2008, 112, 7123-7131.

A Molecular Dynamics Study to Investigate the Effect of Chemical Substitutions of Methionine35 on the Secondary Structure of the Amyloid Beta (Aß(1-42)) Monomer in Aqueous Solution  
L. Triguero, R. Singh and Rajeev Prabhakar, Journal of Physical Chemistry B2008,112, 2159-2167.

Insights into the Mechanism of H2O2-based Olefin Epoxidation Catalyzed by the Lacunary [g-(SiO4)W10O32H4]4- and di-V-substituted-g-Keggin [g-1,2 -H2SiV2W10O40]4- Polyoxometalates. A Computational Study 
Rajeev Prabhakar, K. Morokuma, Y. V. Geletii, C. L. Hill, D. G. Musaev,Computational Modeling for Homogenous and Enzymatic Catalysis. Ed. D. G. Musaev and K. Morokuma, Wiley-VCH Verlag GmbH & Co. 20081-24.

Computational Insights into the Structural Properties and Catalytic Functions of Selenoprotein Glutathione Peroxidase (GPx)
Rajeev Prabhakar, K. Morokuma, D. G. Musaev, Computational Modeling for Homogenous and Enzymatic Catalysis. Ed. D. G. Musaev and K. Morokuma, Wiley-VCH Verlag GmbH & Co. 2008215-229.

2007

Parameter Calibration of Transition metal element for the Spin Polarized Self-Consistent-Charge Density-Functional Tight-Binding (DFTB) Method: Sc, Ti, Fe, Co and Ni. 
G. Zheng, H. Witek, P. Bobadova-Parvanova, S. Irle, D. G. Musaev, Rajeev Prabhakar, K. Morokuma, M. Lundberg, M. Elstner, V. Köhler, T. Frauenheim.Journal of Chemical Theory and Computation 2007, 3(4), 1349-1367.

2006

Peroxinitrite Reductase Activity of Selenoprotein Glutathione Peroxidase (GP x): A Density Functional Study
Rajeev Prabhakar, K. Morokuma, and D. G. Musaev Biochemistry 2006, 45 (22), 6967-6977.

Insights into the Mechanism of Selective Olefin Epoxidation Catalyzed by [gama-(SiO 4)W 10O 32H 4] 4-. A Computational Study Rajeev Prabhakar, K. Morokuma, Craig L. Hill and D. G. Musaev Inorganic Chemistry 2006, 45:5703-5709.

Is Protein Surrounding the Active-Site Critical for Hydrogen Peroxide Reduction by Selenoprotein Glutatione Peroxidase (GPx)? An ONIOM Study 
Rajeev Prabhakar, T. Vreven, M. J. Frisch, K. Morokuma, and D. G. Musaev 
Journal of  Physical Chemistry B 2006, 110, 13608-13613.
 
A DFT Study of the Mechanism of Ni Superoxide Dismutase (NiSOD): Role of the Active Site Cysteine-6 Residue in the Oxidative Half-Reaction 
Rajeev Prabhakar, K. Morokuma, and D. G. Musaev Journal of Computational Chemistry 2006, 27:1438-1445.

2005 
A Density Functional Theory (DFT) study of the spin forbidden dioxygen activation in Monoamine Oxidase B (MAO B)
Rajeev Prabhakar, M. Li, D. G. Musaev, K. Morokuma, and D. E. EdmondsonFlavins and Flavoproteins 2005, 127-131.

Elucidation of the Mechanism of Selenoprotein Glutathione Peroxidase (GPx) Catalyzed Hydrogen Peroxide Reduction by two Glutathione Molecules: A Density Functional Study
Rajeev Prabhakar, T. Vreven, K. Morokuma, and D. G. Musaev Biochemistry 2005, 44(35) 11864-11871. 

A Comparative Study of Various Computational Approaches in Calculating the Structure of Pyridoxal 5 ’– Phosphate (PLP) Dependent beta-Lyase Protein. The Importance of Protein Environment
Rajeev Prabhakar , K. Morokuma, and D. G. Musaev Journal of Computational Chemistry 2005, 26(5) 443-446.

2004
Does the Active Site of Mammalian Glutathione Peroxidase (GPx) Contain Water
Molecules? An ONIOM Study
Rajeev Prabhakar, D. G. Musaev, I. V. Khavrutskii, and K. Morokuma Journal of  Physical Chemistry B 2004, 108(34), 12643-12645.

A DFT study of the Mechanism for the biogenesis of cofactor topaquinone (TPQ) in Copper Amine Oxidases (CAOs)
Rajeev Prabhakar and Per E.M. Siegbahn Journal of American Chemical Society2004, 107(16); 3944 -3953.

Spin transition during H 2O 2 formation in the Oxidative Half-Reaction of Copper amine Oxidases (CAOs)
Rajeev Prabhakar, Per E.M. Siegbahn, Boris F. Minaev and Hans Ågren Journal of Physical Chemistry B 2004, 108, 13882-13892.