Huntington The specific aims are: 1. To investigate the structural role of the N17 headpiece in huntingtin aggregation. ! Previous MD simulations of the isolated N17 headpiece suggest that it is highly helical, and adopts two highly populated conformations consisting of one and two amphipathic helices. We will: a. Perform molecular dynamics simulations of N17-polyQ aggregation on Folding@home using Markov state models. We will investigate our hypothesis that burial of multiple N17 hydrophobic surfaces initiates aggregation of the polyQ tracts by positioning them correctly relative to each other. Based on the simulations, mutations in N17 will be proposed that would be expected to inhibit Htt aggregation. b. N17 mutations computationally predicted to disrupt aggregation will be experimentally verified, via a collaboration with Judith Frydman

Public Health Relevance

Lay description:! ! Huntington

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32NS073353-02
Application #
8262678
Study Section
Special Emphasis Panel (ZRG1-F03B-H (20))
Program Officer
Sutherland, Margaret L
Project Start
2011-03-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$52,190
Indirect Cost
Name
Stanford University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305