With this award, the Chemistry of Life Processes program is supporting the research of Professor James Nowick of the Department of Chemistry at the University of California, Irvine to design, synthesize and study macrocyclic model systems to better understand peptide assembly and aggregation. While proteins in their folded states have been widely studied by structural biologists, it is becoming increasingly clear that their poorly understood misfolded and aggregated states are also of critical importance in biology. Chemical model systems provide an ideal way to better study these complex states. The model systems being developed here will allow the investigation of edge-to-edge hydrogen bonding and face-to-face hydrophobic interactions, particularly in beta-sheet-like assemblies. Because the model systems are macrocycles that interact in a controlled fashion, it may be possible to use the systems developed here to control and modulate peptidyl secondary structure and eventually protein aggregation.
A better understanding of molecular assembly and aggregation in beta-sheet-like structures could have broad scientific impact, well beyond this project, in chemistry and biology. Educational components of this project include the cross-disciplinary training of graduate and undergraduate students in bioorganic and peptide model chemistry. In addition, the PI and his students will continue in their efforts to spark interest in chemistry and science at the K-12 level through the "UCI Chemistry Outreach Program." The PI initiated this program and it has now reached thousands of K-12 students over the past two decades.
Proteins are the primary actors in life's processes. Proteins make up the inner workings of cells and the skin an hair that cover out bodies. They are the enzymes that carry out biochemical transformations and the structural frameworks of muscle and other tissue. Proteins -- and their smaller cousins called peptides -- are designed to interact with each other, fitting together and sticking to each other in controlled fashions to effect the workings of life. Sometimes interactions among proteins go awry or at least occur in ways that we do not yet understand. They clump together to form aggregates that are damaging to cells. These aggregates are found in Alzheimer's disease, type 2 diabetes, and mad cow disease and it's human equivalent Creutzfeldt-Jacob disease. We do not fully understand the role of these rogue proteins in human disease or all of the ways in which the proteins clump together. This project set out to learn more about how peptides and proteins clump together. The approach that our laboratory took was to make peptides containing components not found in Nature that allow them to interact in a controlled fashion so that we could see precisely how they clump together. First we learned how use chemical synthesis to make peptides not found in Nature that interact in a controlled fashion. Then we used powerful tools like nuclear magnetic resonance spectroscopy (NMR) and X-ray crystallography to learn how the peptides and proteins interact. From these studies we are starting to better understand the molecular basis for proteins clumping together. Getting the next generation excited about science and chemistry has always been integral to my laboratory's working. As part of this project, we have continued to run the UCI Chemistry Outreach Program in which teams of graduate and undergraduate students visit K-12 schools to perform exciting demonstrations and talk to kids about chemistry. During the period of the project, we have reached about 8000 kids through visits to K-12 schools, mostly at the elementary school level.
