According to amyloid hypothesis the assembly of Abeta peptides into fibrils plays a central role in Alzheimer's disease. Recent experiments suggest that not only Abeta amyloid fibrils, but also Abeta oligomers are potent neurotoxic agents. However, due to complexity of amyloid assembly the associated molecular mechanisms remain poorly understood. The current proposal targets two distinct mechanisms of Alzheimer's amyloidogenesis - the formation of Abeta oligomers and the elongation of preexisting Abeta fibrils by deposition of individual peptides. The main questions of the project are how do these mechanisms of Alzheimer's amyloidogenesis manifest themselves on a single molecule level? Is it possible to develop a combined microscopic description of fibril growth and oligomer assembly, which together represent major events in Abeta amyloidogenesis? What is the molecular basis of anti-aggregation effect produced by certain non-steroidal anti-inflammatory drugs (NSAID)? To answer these questions a molecular model of the pathways of Abeta amyloid assembly will be developed. The proposed work relies on high-end parallel computing and multi-scale molecular modeling. To overcome computational challenges new protein model and new sampling algorithms are employed. Cross-validation strategies to reduce computational artifacts are incorporated in the research plan. The biomedical significance of the proposed work is that the knowledge of molecular mechanisms of Abeta aggregation can be used to devise strategies to control the levels of soluble and fibrillized Abeta peptides. In particular, the project findings will be useful in the design of new NSAID derivatives with stronger anti-aggregation propensity and Abeta imaging efficiency.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MDCN-K (51))
Program Officer
Refolo, Lorenzo
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
George Mason University
Biostatistics & Other Math Sci
Schools of Arts and Sciences
United States
Zip Code
Kim, Seongwon; Chang, Wenling E; Kumar, Rashmi et al. (2011) Naproxen interferes with the assembly of A? oligomers implicated in Alzheimer's disease. Biophys J 100:2024-32
Lockhart, Christopher; Kim, Seongwon; Kumar, Rashmi et al. (2011) Does amino acid sequence determine the properties of Aýý dimer? J Chem Phys 135:035103
Kim, Seongwon; Takeda, Takako; Klimov, Dmitri K (2010) Mapping conformational ensembles of aýý oligomers in molecular dynamics simulations. Biophys J 99:1949-58
Takeda, Takako; Kumar, Rashmi; Raman, E Prabhu et al. (2010) Nonsteroidal anti-inflammatory drug naproxen destabilizes A? amyloid fibrils: a molecular dynamics investigation. J Phys Chem B 114:15394-402
Chang, Wenling E; Takeda, Takako; Raman, E Prabhu et al. (2010) Molecular dynamics simulations of anti-aggregation effect of ibuprofen. Biophys J 98:2662-70
Kim, Seongwon; Takeda, Takako; Klimov, Dmitri K (2010) Globular state in the oligomers formed by Abeta peptides. J Chem Phys 132:225101
Takeda, Takako; Chang, Wenling E; Raman, E Prabhu et al. (2010) Binding of nonsteroidal anti-inflammatory drugs to Abeta fibril. Proteins 78:2849-60
Takeda, Takako; Klimov, Dmitri K (2010) Computational backbone mutagenesis of Abeta peptides: probing the role of backbone hydrogen bonds in aggregation. J Phys Chem B 114:4755-62
Takeda, Takako; Klimov, Dmitri K (2009) Replica exchange simulations of the thermodynamics of Abeta fibril growth. Biophys J 96:442-52
Takeda, Takako; Klimov, Dmitri K (2009) Probing energetics of Abeta fibril elongation by molecular dynamics simulations. Biophys J 96:4428-37

Showing the most recent 10 out of 15 publications