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.
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.
|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|
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|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|