PROTEIN AGGREGATION AND AMYLOIDAL FIBRIL FORMATION IN NANOPOLYMERIC

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Recent experimental studies have shown that various degenerative diseases are associated with deposition in the body tissues of insoluble protein aggregates that have a particular (3-sheet conformation. These aggregates have been termed amyloidal fibrils. It has been proposed that the formation of amyloidal fibrils is determined by the nature of the intermediate unfolding species. Moreover, recent experimental studies have shown that amyloidal fibril formation might be favor when proteins are confined in membranes. However, not enough theoretical or experimental considerations have been focused on elucidate the extend of the effect and/or role that membranes plays in the amyloidal fibril formation. This becomes an important issue to address since polymeric protein delivery systems provide a suitable environment for protein fibrillization to occur. We propose to develop state-of-the-art computer simulations and experimental techniques to study the formation of the amyloidal fibrils under a series of well-defined and biologically relevant conditions. Specifically, coarse-grained and all-atom potentials will be used and/or develop to properly describe the interparticle forces. Monte Carlo and Molecular Dynamic simulations will be coupled to appropriate sampling techniques to determine the structure and stability of the aggregates. Experimental techniques will be designed and implemented to characterize the extend to which a given peptide will eventually form fibrils or amorphous aggregates. The results are expected to uncover basic trends (such as amino acid sequence, charge, ad hydrophobicity) on the molecular description of amyloidal fibril formations. These basic trends will permit the development of prediction capabilities for the possible fibril formation given the system (protein structure) and the experimental set-up (solvent, ionic strength, thermodynamic state, and presence of a membrane). By recognizing membrane compliance as an important additional consideration, we expect to deepen our understanding of the role of membrane composition and interface as a possible controller of fibrilar formation. Examples of these systems are insulin, lysozime, myoglobin, and STVIIE. Polymeric membranes of various composition, that provide a range of polarities, will be used.