The association of proteins of known sequence is believed to be the principal cause of Alzheimer's and other neurodegenerative diseases. Upon aggregation, certain proteins form fibrillar structures that have been implicated as necessary pathogenic factors. The mechanisms of aggregation of polypeptide chains that lead to the formation of fibrillar structures is largely unknown. To date, experiments have provided only low resolution structures of the aggregated states of certain plaque forming peptides. In addition, the nature of conformational fluctuations leading to aggregation of polypeptide chains has not been fully elucidated. The long-term goal of this research is the elucidation of the fundamental principles responsible for polypeptide association and fibrillar formation. To achieve this goal, the PI's propose a multifaceted approach that includes the development and use of novel computational methods. They will employ all atom molecular dynamics simulations to probe the aggregation mechanism in Abeta-peptide (structured as monomeric peptide in water) and human amylin (structureless in the monomeric state). This will enable them to monitor in detail the nature of initiating (nucleating) structures responsible for fibril formation. The complete characterization of the peptide association pathways will be achieved through the direct simulation of protein-protein association, in conjunction with the application of reaction pathway algorithms to explore protein dimerization and fibril elongation. To discover the general principles governing amyloid formation, Dr. Straub will supplement the detailed molecular dynamics simulations with studies involving coarse grained models of polypeptides. This is necessary due to the prohibitively long times required for all atom simulations to examine a large number of peptide sequences. Using off-lattice and lattice models (with side chains), Dr. Straub proposes to examine the phase behavior, energetics and kinetics of peptide association. A further objective is to probe the role of folding intermediates in facilitating aggregation. Simplified models will be used to examine how the details of peptide sequence and initial conditions influence fibril formation. Preliminary results suggest that both atomistic and coarse-grained models can be effective tools for exploring the details of protein dynamics and equilibriums that arise in the aggregation process. The proposed combination of computational approaches will lead to a conceptual understanding of aggregation, at the molecular level, in polypeptide chains that is central to the understanding of amyloid diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS041356-01
Application #
6319301
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Program Officer
Murphy, Diane
Project Start
2001-04-01
Project End
2005-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
1
Fiscal Year
2001
Total Cost
$309,220
Indirect Cost
Name
Boston University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Boston
State
MA
Country
United States
Zip Code
02215
Rivera, Eva; Straub, John; Thirumalai, D (2009) Sequence and crowding effects in the aggregation of a 10-residue fragment derived from islet amyloid polypeptide. Biophys J 96:4552-60
Tarus, Bogdan; Straub, John E; Thirumalai, D (2005) Probing the initial stage of aggregation of the Abeta(10-35)-protein: assessing the propensity for peptide dimerization. J Mol Biol 345:1141-56
Buchete, N-V; Straub, J E; Thirumalai, D (2004) Continuous anisotropic representation of coarse-grained potentials for proteins by spherical harmonics synthesis. J Mol Graph Model 22:441-50
Buchete, Nicolae-Viorel; Straub, John E; Thirumalai, Devarajan (2004) Orientational potentials extracted from protein structures improve native fold recognition. Protein Sci 13:862-74
Dima, Ruxandra I; Thirumalai, D (2004) Proteins associated with diseases show enhanced sequence correlation between charged residues. Bioinformatics 20:2345-54
Klimov, D K; Straub, John E; Thirumalai, D (2004) Aqueous urea solution destabilizes Abeta(16-22) oligomers. Proc Natl Acad Sci U S A 101:14760-5
Dima, Ruxandra I; Thirumalai, D (2004) Probing the instabilities in the dynamics of helical fragments from mouse PrPC. Proc Natl Acad Sci U S A 101:15335-40
Buchete, N-V; Straub, J E; Thirumalai, D (2004) Development of novel statistical potentials for protein fold recognition. Curr Opin Struct Biol 14:225-32
Massi, Francesca; Straub, John E (2003) Structural and dynamical analysis of the hydration of the Alzheimer's beta-amyloid peptide. J Comput Chem 24:143-53
Klimov, Dmitri K; Thirumalai, D (2003) Dissecting the assembly of Abeta16-22 amyloid peptides into antiparallel beta sheets. Structure 11:295-307

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