Recognition and Presentation of Alpha Helices using Nanoparticle Receptors

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DESCRIPTION (provided by applicant): Surface recognition of proteins provides access to new therapeutic and diagnostic strategies. In our proposed research we will target helix-cleft protein-protein interactions such as p53-HDM2 using gold nanoparticle-based synthetic receptors. In these receptors, the nanoparticle monolayer will play an active role in the recognition process, exploiting the size scale (6-10 nm in diameter) and the ability of nanoparticles to be templated to target molecules. We will pursue two different strategies in our research: 1) Presentation of helices for the targeting of complementary protein clefts (e.g. HDM2); 2) Templation of the nanoparticles to helices for recognition of exposed helices. The proposed research features three specific Aims. These aims are interrelated, bringing to bear synthetic, physical and biophysical methodologies. In these Aims, we will: Aim 1: Determine the scope and events involved in electrostatic binding of nanoparticles and their templation to ?-helices, focusing on the optimization of helix recognition. Aim 2: Covalently link the supramolecular peptide-particle assemblies developed in Aim 1, and target these conjugates to cleft-bearing proteins, including the p-53 binding domain of HDM2. These studies will focus on: 1) The ability of the particle to stabilize the helical structure of the peptide; 2) The use of the particle monolayer to enhance the affinity of the receptors and to control the structure of the bound protein. Aim 3: Use nanoparticles as sensors for biomedically-relevant proteins. In these studies, particles will be templated to fluorophore-tagged peptides. The complexation of the peptide by the particle will quench the fluorophore. Fluorescent enhancement upon displacement of the peptide by the target protein will then be used to transduce binding. The selectivity of the protein-particle binding process will be applied in an array format to provide "chemical nose" sensing of proteins. Relevance: This research focuses on the creation of potential anti-cancer therapeutics and the detection of protein biomarkers for diagnosis of cancer and other disease states.