The subject of this research project is to develop and experimentally validate a novel computational approach to analyze structural ensembles in proteins and peptides that are largely monomeric and unstructured in solution but have the ability to form amyloid fibers. The tools for all-atom computer simulations for such systems are currently underdeveloped which has significant consequences for our understanding of the molecular determinants of amyloidosis. In order to put the development of computational tools in a biological context, we will apply them to a 39-residue peptide from human acidic prostatic phosphatase that is known to form fibrillar structures. These fibrillar structures have been shown to be important for enhancement in viral infectivity of human cells. The computational study will be validated by a battery of experimental methods including NMR, atomic force microscopy, fluorescence and circular dichroism spectroscopies, and hydrogen exchange mass spectroscopy.

Public Health Relevance

Amyloid fibrils are pathogenically associated with a range of debilitating human diseases. Understanding the role of the structure-sequence relationship in amyloidogenic proteins and peptides will provide detailed mechanistic insight into the process of amyloidosis and will aid design of therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21GM101134-01
Application #
8279567
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Wehrle, Janna P
Project Start
2012-06-01
Project End
2014-04-30
Budget Start
2012-06-01
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$232,220
Indirect Cost
$82,220
Name
Rensselaer Polytechnic Institute
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
002430742
City
Troy
State
NY
Country
United States
Zip Code
12180
French, Kinsley C; Roan, Nadia R; Makhatadze, George I (2014) Structural characterization of semen coagulum-derived SEM1(86-107) amyloid fibrils that enhance HIV-1 infection. Biochemistry 53:3267-77
Shanmuganathan, Aranganathan; Bishop, Anthony C; French, Kinsley C et al. (2013) Bacterial expression and purification of the amyloidogenic peptide PAPf39 for multidimensional NMR spectroscopy. Protein Expr Purif 88:196-200