INTELLECTUAL MERIT: It is proposed to use a single molecule technique to study the fundamentals of peptide self-assembly in unprecedented detail. Self-assembly of peptides underlies all phases of biological systems including protein folding, molecular machines, and hierarchical structures of biological materials. Current methods, such as x-ray crystallography and nuclear magnetic resonance, provide structural details of biological molecules, but they are largely limited to a static or ensemble averaged view rather than dynamic one. The PI will overcome these limitations by using a single molecule technique with high spatial and force resolution together with novel engineered single molecule constructs to study the dynamic self-assembly behavior at the single molecule and nanoscale level. At the single molecule level, he will study self-assembly of amyloid beta and tau using optical tweezers. Amyloid beta and tau self-assemble into nanofibers that provide an excellent platform for novel bioinspired nanostructures. Initial results on a single protein domain showed that the conformational dynamics can be studied in an extremely detailed manner using custom-built optical tweezers. The combination of optical tweezers and novel single molecule constructs are likely to provide new fundamental information about dynamic self-assembling behaviors of the amyloid beta and tau molecule in a direct manner. The PI will directly measure interactions between amyloid beta molecules and monitor how their interactions and conformations change under different environments. This will permit making an unambiguous determination of the specific environments that facilitate dimer formation and the molecular sites of the interactions. He will also test how small molecules and site-directed mutagenesis influence the self-assembly process and will determine the effects of these factors on the rates of conformational changes and the final nanostructures. At the nanoscale level, he will use a silk-elastin peptide polymer to study surface facilitated self-assembly. It is anticipated that the exact mechanism of this behavior can be analyzed in detail.
BROADER IMPACTS: The PI has developed an undergraduate course entitled Biomaterials, intended primarily for undergraduate students in engineering and physical sciences. Lectures address principally the structures of natural and synthetic biomaterials, polymer physics, self-assembly, interactions between biopolymers, and a survey of modern biophysical techniques, including atomic force microscopy and optical tweezers. This course has a strong laboratory component that will be integrated not only with these lectures but also with an NSF-supported REU program in the Department. REU students will have the opportunity to probe gene delivery mechanisms using optical tweezers and to develop new experimental protocols for force measurements and data analysis methods. The PI also plans to teach a new graduate course called Nanomechanics of Biomaterials in which molecular design parameters that determine the nanomechanical properties of biomaterials will be covered in depth. This course will familiarize graduate students with current physical characterization tools and equip them with sophisticated knowledge of intermolecular forces and nanostructures that dictate the physiological role of biomaterials. Furthermore, he will continue his efforts to broaden participation of women and minorities in science and engineering. Specifically he has designed an AFM laboratory for blind high school students to educate them in the area of nanotechnology through a summer academy conducted by the Jernigan Institute National Center for Blind Youth and Science.
