This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).
INTELLECTUAL MERIT: The goal of the proposed research is to create a new archetype in protein design that will enable bottom-up self-assembly of nanostructured devices and materials. The intent is to create a library of asymmetric, heteromeric interactions mediated by parallel beta-sheets. Many proteins display domains with parallel â-sheets on one or more of their exterior surfaces. Successful design of such interfaces would therefore result in a library of protein-protein interactions that can be transferred from one topological arrangement to another. The sequence of research aims proposed here is as follows: (1) Develop a library of pairs of short peptides (< 10 residues) that form beta-sheet-rich amyloid fiber structures on mixing, but do not otherwise self-associate. Generation and screening of candidate peptides will be based in part on combinatorial peptide syntheses, and in part, on examining emerging atomic structures of proven parallel beta-sheet amyloids, e.g. the Abeta peptide from Alzheimer?s disease. (2) Amyloid derived sequences will then be mapped onto the solvent exposed surface of a stably folded and monomeric globular protein. The protein proposed to serve as initial scaffold displays three symmetry related parallel beta-sheets on its surface. Symmetry is capitalized upon to generate periodic structures that facilitate screening, and serve as a novel system for generating self-assembling monolayers from a folded and globular precursor. (3) Asymmetric variants of the scaffold used in (2) to will be developed and used to present two or more alternative interaction motifs on the protein surfaces. These designs will enable structural and thermodynamic characterization of the interactions. An understanding of the geometries and energies is essential for the correct prediction of the form, fidelity and stability of higher order structures built from these 1-10nm sized starting materials.
BROADER IMPACTS: Successful implementation of the project will result in novel nanostructure design tools accessible to a wide range of material scientists and macromolecular engineers. Student training on this project is multidisciplinary, requiring a range of spectroscopic, imaging and structure determination techniques. Undergraduate summer projects are included in the project and will be open to students in all departments at Yale participating in the Yale Institute for Nanotechnology. The project will enable the straightforward and safe production of visually apparent amounts of materials from nano-scaled interactions. It is envisaged that solenoid interface domains will be able to produce useful demonstrations in a lecture setting, thus offering opportunity for a greater public understanding of nano-technology. For example, heteromeric interfaces formed by mixing of solenoids can be designed to form structures with periodic, nano-scale changes in refractive index. Such photonic materials are visually appealing and can be related to commonly observed materials (e.g. opals). Thus, light interactions of the generated materials in simple scattering experiments (and more sophisticated photonics) will be demonstrable in lecture settings. The PI is involved in outreach to K-12 schools and will provide hands-on experience for elementary school students and more advanced activities for upper grade students.
