个人简介

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

研究领域

Computational chemistry, enzyme catalyzed reactions, neurodegenerative disorders and drug designing

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.

近期论文

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A Compact Molecule for Redirecting Amyloid-ß Peptides into Nontoxic, Off-pathway Aggregates. Younwoo Nam, Richard A. Kerr, Jeffrey S. Derrick, Hyuck Jin Lee, Kristy L. Peck, Mehmet Ozbil, Kyle J. Korshavn, Ayyalusamy Ramamoorthy, Rajeev Prabhakar, Jason Shearer, Brandon T. Ruotolo, Mi Hee Lim. Nature Chemistry, 2015, submitted. Dynamic protein interactions drive neuronal development. Nima Sharifai, Tzyy-Chyn Deng, Hasitha Samarajeewa, Maria Boullina, Charles Yu, Kenneth H. Wan, Tingting Zhang, Sarun Glyanon, James D. Baker, Chittanon Buranachai, Michael D. Kim, Daichi Kamiyama, Vance P. Lemmon, Stefan Wuchty, Rajeev Prabhakar, Gavriil Tsechpenakis, Susan E. Celniker, Akira Chiba. Nature, 2015, submitted. An Extended Polyanion Activation Surface in Insulin Degrading Enzyme. Eun Suk Song, Mehmet Ozbil, Tingting Zhang, Michael Sheetz, David Lee, Danny Tran, Sheng Li, Rajeev Prabhakar, Louis B. Hersh and David W. Rodgers. PLOS ONE, 2014, submitted. Hybrid peptide ATCUN-sh-Buforin: Influence of the ATCUN charge and stereochemistry on antimicrobial activity. M. Daben Libardo, Thomas J. Paul, Rajeev Prabhakar, Alfredo Angeles-Boza. Biochimie, 2015, In Press. Theoretical Insights into the Functioning of Metallopeptidases and Their Synthetic Analogues. Tingting Zhang, Mehmet Ozbil, Arghya Barman, Thomas J. Paul, Ram Prasad Bora, and Rajeev Prabhakar. Accounts of Chemical Research, 2015, 48(2), 192-200. (Link) Role of hydrogen bonds in molecular packing of photoreactive crystals: templating photodimerization of protonated stilbazoles in crystalline state with a combination of water molecules and chloride ions. Barnali Mondal, Tingting Zhang, Rajeev Prabhakar, Burjor Captain and V. Ramamurthy. Photochemical & Photobiological Sciences, 2014, 13, 1509-1520. (Link) Computational Insights into Substrate and Site Specificities, Catalytic Mechanism and Protonation States of the Catalytic Asp Dyad of ß-Secretase (BACE1). Arghya Barman and Rajeev Prabhakar. Scientifica, 2014, doi:10.1155/2014/598728 (Link) Peptide Hydrolysis by Metal-Cyclen Complexes and Their Analogues: Insights from Theoretical Studies. Tingting Zhang, Xiaoxia Zhu, Rajeev Prabhakar. Organometallics, 2014, 33(8), 1925–1935. (Link) Mechanistic Insights into Metal (Pd2+, Co2+ and Zn2+) - Beta Cyclodextrin Catalyzed Peptide Hydrolysis: A QM/MM Approach. Tingting Zhang, Xiaoxia Zhu, Rajeev Prabhakar. Journal of Physical Chemistry B, 2014, 118(15), 4106–4114. (Link) Pb(II)-promoted Amide Cleavage: Mechanistic Comparison to a Zn(II) Analog. Eric S. Elton, Tingting Zhang, Rajeev Prabhakar, Atta M. Arif, and Lisa M. Berreau. Inorganic Chemistry, 2013, 52(19), 11480-11492. (Link) Unraveling the Photoluminescence Response of Light-Switching Ruthenium(II) Complexes Bound to Amyloid-β. Nathan Cook, Mehmet Ozbil, Christina Katsampes, Rajeev Prabhakar, Angel Martí. Journal of American Chemical Society, 2013, 135(29), 10810-10816. (Link) Elucidating the Catalytic Mechanism of β-secretase (BACE1): A Quantum Mechanics/Molecular Mechanics (QM/MM) Approach. Arghya Barman and Rajeev Prabhakar. Journal of Molecular Graphics and Modelling, 2013, 40, 1-9. (Link) Experimental and Computational Evidence of Metal-O2 Activation in a Copper Amine Oxidase. Yi Liu, Arnab Mukherjee, Nadav Nahumi, Mehmet Ozbil, Doreen Brown, Alfredo M. Angeles-Boza, David M. Dooley, Rajeev Prabhakar, and Justine P. Roth. Journal of Physical Chemistry B, 2013, 117(1), 218-229. (Link) Hydrocarbons Depending on the Chain Length and Head Group Adopt Different Conformations Within a Water-soluble Nanocapsule: 1H NMR and Molecular Dynamics Studies. Rajib Choudhury, Arghya Barman, Rajeev Prabhakar and V. Ramamurthy. Journal of Physical Chemistry B, 2013, 117(1), 398-407. (Link) Perspective: Computational Insights into Dynamics of Protein Aggregation and Enzyme-Substrate Interactions. Mehmet Ozbil, Arghya Barman, Ram Prasad Bora and Rajeev Prabhakar. Journal of Physical Chemistry Letters, 2012, 3, 3460-3469. (Link) Protonation States of the Catalytic Dyad of β-Secretase (BACE1) in the Presence of Chemically Diverse Inhibitors: A Molecular Docking Study. Arghya Barman and Rajeev Prabhakar. Journal of Chemical Information and Modeling, 2012, 52(5), 1275-1287. (Link) Disulfide Bridges Remain Intact While Native Insulin converts Into Amyliod Fibrils. Dmitry Kuriuski, Jacqueline Washington, Mehmet Ozbil, Rajeev Prabhakar, Alexander Shektman, and Igor K. Lednev. PLoS ONE, 2012, 7(6), e36989. (Link) Dimerization of the Full-Length Alzheimer Amyloid β-peptide (Aβ42) in Explicit Aqueous Solution: A Molecular Dynamics Study. Xiaoxia Zhu, Ram Prasad Bora, Arghya Barman, Rajiv Singh, and Rajeev Prabhakar. Journal of Physical Chemistry B, 2012, 116(15), 4405-4416. (Link) Mechanism of Peptide Hydrolysis by Co-catalytic Metal Centers Containing Leucine Aminopeptidase Enzyme: A DFT Approach. Xiaoxia Zhu, Arghya Barman, Mehmet Ozbil, Tingting Zhang, Shanghao Li, and Rajeev Prabhakar. Journal of Biological Inorganic Chemistry, 2011, 17(2), 209-222. (Link) Loss of Cleavage at β’-Site Contributes to the Apparent Increase of Aβ Secretion by BACE1-GPI Proccessing of APP. Kulandaivelu S. Vetrivel, Arghya Barman, Ying Chen, Phuong D. Nguyen, Steven L. Wagner, Rajeev Prabhakar, and Gopal Thinakaran. Journal of Biological Chemistry, 2011, 286, 26166-26177. (Link)