This is a proposal to combine two-dimensional infrared spectroscopy with oxidative footprinting / mass spectrometry and molecular mechanics simulation to answer key questions about the formation and structure of amyloid beta protein fibrils. There are two specific aims: 1. Correlate structure and morphology in amyloid fibrils. 2. Characterize the development of structure in oligomeric forms of A?. This project is an interdisciplinary collaboration between a physician-pharmacologist investigating the pathology of Alzheimer's disease, and a chemical physicist pioneering novel spectroscopic methods. We will be applying an emerging, powerful, and versatile technology for the first time to understanding the structural biology of an important biomedical problem. This research will make use of instrumentation in the Ultrafast Optical Processes Laboratory - an NIH Research Resource at the University of Pennsylvania. This laboratory was established to develop novel technologies involving infrared spectroscopy for the study of biological macromolecules, and to make advanced instrumentation and expertise available for collaborative projects of this type.

Public Health Relevance

This is a proposal to combine two-dimensional infrared spectroscopy with oxidative footprinting / mass spectrometry and molecular mechanics simulation to answer key questions about the formation and structure of amyloid beta protein fibrils.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM076201-06
Application #
8328956
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Smith, Ward
Project Start
2007-04-15
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
6
Fiscal Year
2012
Total Cost
$311,574
Indirect Cost
$113,574
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ma, Jianqiang; Komatsu, Hiroaki; Kim, Yung Sam et al. (2013) Intrinsic structural heterogeneity and long-term maturation of amyloid * peptide fibrils. ACS Chem Neurosci 4:1236-43
Yeung, Priscilla S-W; Eskici, Gozde; Axelsen, Paul H (2013) Infrared spectroscopy of proteins in reverse micelles. Biochim Biophys Acta 1828:2314-8
Yeung, Priscilla S-W; Axelsen, Paul H (2012) The crowded environment of a reverse micelle induces the formation of ?-strand seed structures for nucleating amyloid fibril formation. J Am Chem Soc 134:6061-3
Kim, Yung Sam; Liu, Liu; Axelsen, Paul H et al. (2009) 2D IR provides evidence for mobile water molecules in beta-amyloid fibrils. Proc Natl Acad Sci U S A 106:17751-6
Kim, Yung Sam; Liu, Liu; Axelsen, Paul H et al. (2008) Two-dimensional infrared spectra of isotopically diluted amyloid fibrils from Abeta40. Proc Natl Acad Sci U S A 105:7720-5