This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Huntington?s disease is linked to the insertion of glutamine (Q) in the protein huntingtin, resulting in polyglutamine (polyQ) expansions that self-associate to form aggregates. The length of the expansion correlates with the onset of Huntington?s disease. While polyQ aggregation has been the subject of intense study, a correspondingly thorough understanding of individual polyQ chains is lacking. Atomic resolution structural information for polyQ chains in aqueous solution is still absent from the literature. We have discovered experimentally that polyQ chains exhibit unexpected extremely high mechanical stabilities and in a preliminary study we were able to sample a small number of polyQ chain conformations that were similarly resilient. We propose to generate sufficiently long runs on ANTON that will explain the existence of such mechanically resilient conformations, what their structures are, and how they aggregate. Mechanical resilience allows these disordered structures to survive for a sufficiently long time for them to aggregate and resist proteasomes. In the proposed research we will investigate the conformation space of different length polyQs and their aggregation using ANTON.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
3P41RR006009-20S1
Application #
8364205
Study Section
Special Emphasis Panel (ZRG1-BCMB-Q (40))
Project Start
2011-09-15
Project End
2013-07-31
Budget Start
2011-09-15
Budget End
2013-07-31
Support Year
20
Fiscal Year
2011
Total Cost
$1,094
Indirect Cost
Name
Carnegie-Mellon University
Department
Biostatistics & Other Math Sci
Type
Schools of Arts and Sciences
DUNS #
052184116
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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