The objective of this study is to determine the effect of the presence of an interface on the ability of peptides to form amyloid deposits. The formulation and testing of the hypotheses presented in this proposal will build the foundations for making further advances in the prevention and/or cure of amyloid diseases. The proposed research is divided into five tasks: 1) Formulation of the model and adaptation of a MC suite already developed in our laboratory; 2) Use of the simulation package to study the aggregation of peptides in bulk and at solid liquid interfaces; 3) Synthesis of a family peptides and fabrication of biological membrane mimics; 4) Experimental studies of the stability of the peptides in bulk under different solvent conditions; 5) Experimental studies of the formation of amyloid deposits at the solid/liquid interface. The following questions will be addressed: 1) Is the formation of amyloid deposits a truly universal phenomenon 2) Does the surface function as a nucleation site and 3) What features of the surface are more likely to induce the formation of aggregates and secondary structure within those aggregates Should the surface be hydrophobic or hydrophilic? Do specific sites on the surface play a dominant role in the formation of the aggregates. Is the presence of a particular pattern at the surface needed for the formation of aggregates To address these questions, the PI will continue with the philosophy that only partial answers can be obtained by research compartmentalized in either experimental or theoretical beans. A well integrated approach consisting of both theoretical (Monte-Carlo simulations) and experimental work (synthesis of new peptides, use of dynamic light scattering, and atomic force microscopy) is more likely to achieve success in answering of these questions.
Intellectual Impact
Pursuing and achieving the goals of this project will impact science and engineering by advancing the knowledge of debilitating diseases and by improving the understanding of protein stability. The overall philosophy of our approach will set standards for the construction of model systems to study biological processes. The development of computer codes and the fact that the codes will be freely available to the rest of the community will advance computational biology. The experimental work proposed will stretch to its limits current experimental techniques, promoting the development of more adequate techniques. The conviction that research in the biological sciences must consist of a combination of carefully planned experiments and sophisticated machine simulations that transpires from the approach will motivate other researchers to take similar avenues.
Broader Impact
This research will lay the foundations for a better understanding of the formation of amyloid fibrils. Because of that, human health sciences and society will benefit from the findings. The P.I. has a solid record as an educator of undergraduate students in his research laboratory. Therefore, relatively heavy undergraduate participation in this project is expected. The P.I. has also been able to attract most (if not all) the minority students that joined the graduate program at the Chemical Engineering Department of Missouri S&T. The P.I. will personally recruit minorities from minority institutions to participate in this project. The project will produce two Ph.D. in Chemical Engineering educated in state of the art techniques and with the necessary expertise to become the educators and researchers of the future. The P.I. will visit regional high schools with the purpose of showing that Chem. Eng. is not a dry discipline by establishing a bridge between biology and engineering. This project is particularly well suited for that purpose because of the clear connection with disease. The P.I. will use return of indirect funds to invite science high school teachers from local schools to work in the P.I. lab during the summer months.
