The Topology of Peptide/Protein Interaction Space

The Topology of Peptide/Protein Interaction Space The Topology of Peptide/Protein Interaction Space We propose to use recent advances in high throughput, array-based synthesis of peptides to create a map of the topology of peptide/protein interaction space. Intellectual Merit. We will do this by using a technology recently developed by Intel to create a set of approximately 200 silicon chips that each contain an array of ~500,000 peptides. The fabrication will be overseen by the Intel team leader, Dr. John Rajasekaran, who invented this technology (now an ASU faculty member) using equipment donated to ASU by Intel. These chips will be exposed to a range of different labeled protein target sequences and the affinity and specificity of the interaction will be determined. These peptide sequences (and sometimes mixtures of sequences) will be chosen such that we obtain both an understanding of the local topology of peptide functional space and a broader view of that space, with two different resolutions. This will be the initial proof of concept experiment in a larger program that will explore the following questions: How large are the functional features of peptide/protein interaction space (large in terms of the range of sequence variation that allows some level of function)? How frequently in peptide space do functional features appear and how are they distributed in terms of clustering, height and breadth? What are the best algorithms for finding and optimizing peptide function? Can one correlate molecular modeling outcomes of peptide structure and dynamics to measured function and use these results to both improve molecular modeling and refine peptide selection more rapidly when searching for specific functions? The EAGER funds will be used to perform the initial array fabrication and analysis. There currently is no data of this type available on this scale. We need to demonstrate the feasibility of the approach in order to apply for a major grant in this area. Broader Impact. The ability to map, in a deterministic sense, the functional topology of peptide space has very far reaching implications. We are driving towards a point in which developing novel molecular function is an algorithmic process that takes full advantage of the power of large libraries and molecular evolution principles, while also leveraging the full power of computational modeling and informatics. This represents a major step in that direction as it allows us to map peptide function on a scale (or at a resolution) greater by about two orders of magnitude than it has been done before. Ultimately, an additional three orders of magnitude should be readily achievable. This program will also provide training for a postdoc and a high school teacher and student. The Biodesign Institute has a Postdoc program that includes career development opportunities as well as individual mentoring. We also run a summer program for High School teachers and students in which they participate in the lab, mentored by one of the lab members (in this case the postdoc).