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.
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.
| LoRicco, Josephine G; Xu, Changmingzi Sherry; Neidleman, Jason et al. (2016) Gallic Acid Is an Antagonist of Semen Amyloid Fibrils That Enhance HIV-1 Infection. J Biol Chem 291:14045-55 |
| Srivastava, Kinshuk R; French, Kinsley C; Tzul, Franco O et al. (2016) Intramolecular diffusion controls aggregation of the PAPf39 peptide. Biophys Chem 216:37-43 |
| 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 |
| French, Kinsley C; Makhatadze, George I (2012) Core sequence of PAPf39 amyloid fibrils and mechanism of pH-dependent fibril formation: the role of monomer conformation. Biochemistry 51:10127-36 |
