Our goal is to obtain an accurate understanding of the mechanism of nucleation and oligomerization in polyglutamine aggregation. Our studies will be based on a combination of molecular simulations and fluorescence correlation spectroscopy (PCS) experiments. Polyglutamine aggregation, a nucleation- dependent process, is of direct relevance to the onset and progression of nine different neurological diseases, including Huntington's disease. Details of nucleation mechanisms are relevant for in vivo aggregation given the toxic given the toxic roles ascribed to early intermediates populated on or off the pathways to formation of large aggregates. To adjudicate between the different proposals for nucleation of polyglutamine aggregation, we need detailed simulations of chain oligomerization in systems containing polyglutamine. Toward this end, we developed an efficient and accurate simulation engine, which allows us to simulate conformational and phase equilibria for multiple polyglutamine molecules of varying lengths. This engine named ABSINTH, for Aggregation of Biomolecules Studied using Implicit Novel Tunable Hamiltonians is based on a new method for modeling mean-field interactions of polypeptides with water and water-mediated interactions within and between polypeptides. We can now test specific hypotheses for nucleation and oligomerization of polyglutamine molecules by seeking answers to questions listed below: 1. Does increasing polyglutamine length stabilize intramolecular 3-sheets or reduce the barrier to the formation of these structures? 2. Are unstable, partially swollen conformations characterized by a critical number of (3-sheet contacts better suited than metastable, compact, (3-sheets for nucleation of polyglutamine oligomerization? 3. How do perturbations in overall solvent quality and sequence context influence conformational fluctuations of polyglutamine and how do these fluctuations alter the phase behavior of polyglutamine? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS056114-01A1
Application #
7264152
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Sutherland, Margaret L
Project Start
2007-04-15
Project End
2011-03-31
Budget Start
2007-04-15
Budget End
2008-03-31
Support Year
1
Fiscal Year
2007
Total Cost
$284,789
Indirect Cost
Name
Washington University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Franzmann, Titus M; Jahnel, Marcus; Pozniakovsky, Andrei et al. (2018) Phase separation of a yeast prion protein promotes cellular fitness. Science 359:
Newcombe, Estella A; Ruff, Kiersten M; Sethi, Ashish et al. (2018) Tadpole-like Conformations of Huntingtin Exon 1 Are Characterized by Conformational Heterogeneity that Persists regardless of Polyglutamine Length. J Mol Biol 430:1442-1458
Fuertes, Gustavo; Banterle, Niccolo; Ruff, Kiersten M et al. (2018) Comment on ""Innovative scattering analysis shows that hydrophobic disordered proteins are expanded in water"". Science 361:
Wang, Jie; Choi, Jeong-Mo; Holehouse, Alex S et al. (2018) A Molecular Grammar Governing the Driving Forces for Phase Separation of Prion-like RNA Binding Proteins. Cell 174:688-699.e16
Staller, Max V; Holehouse, Alex S; Swain-Lenz, Devjanee et al. (2018) A High-Throughput Mutational Scan of an Intrinsically Disordered Acidic Transcriptional Activation Domain. Cell Syst 6:444-455.e6
Posey, Ammon E; Ruff, Kiersten M; Harmon, Tyler S et al. (2018) Profilin reduces aggregation and phase separation of huntingtin N-terminal fragments by preferentially binding to soluble monomers and oligomers. J Biol Chem 293:3734-3746
Holehouse, Alex S; Pappu, Rohit V (2018) Collapse Transitions of Proteins and the Interplay Among Backbone, Sidechain, and Solvent Interactions. Annu Rev Biophys :
Holehouse, Alex S; Pappu, Rohit V (2018) Functional Implications of Intracellular Phase Transitions. Biochemistry 57:2415-2423
Best, Robert B; Zheng, Wenwei; Borgia, Alessandro et al. (2018) Comment on ""Innovative scattering analysis shows that hydrophobic disordered proteins are expanded in water"". Science 361:
Garai, Kanchan; Posey, Ammon E; Li, Xinyi et al. (2018) Inhibition of amyloid beta fibril formation by monomeric human transthyretin. Protein Sci 27:1252-1261

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