Scientific Merit: Thermophilic proteins, primarily extracted from organisms that thrive at very high temperatures, denature at significantly higher temperatures than mesophilic proteins from organisms that live at moderate temperatures. One of the long-standing questions in protein science has been: How do selective pressures, such as environmental temperature, impinge on the evolution of thermal tolerance in proteins? With the advent of proteomic and systems level studies that encompass the complete set of proteins in an organism, the question becomes yet more remarkable: How do cells grown at high temperatures adapt their entire collection of proteins? While existing studies are on individual sets of proteins, several experimental data characterizing different proteomes demand new theoretical modeling and detailed analysis at a much larger scale to unravel broad scale adaptive strategies that different organisms may have utilized to withstand such temperature extremities. Such large scale detailed modeling of numerous proteins will be combined with experimental observations as part of this project. The novel multi-scale research will enable computation of several important, hard to measure, yet analyzed biophysical quantities that are central to protein function and stability, ultimately dictating biology. Thus the relationship of microscopic structural features to protein thermodynamics on a global scale will provide essential clues to protein evolution and engineering.
Broader Impact: The project will impact multiple outreach efforts and new initiatives for education. Concepts of protein science, directly related to this work will be integrated in these outreach activities by incorporating in class material, workshop, engaging demonstrations for general public awareness. Graduate curricula and courses will be designed for the newly launched Molecular and Cellular Biophysics doctoral program at the University of Denver in which quantitative modeling in biology including concepts of protein folding, stability and evolution, will be showcased. Simple concepts derived from this research in the form of puzzles, animations and posters will be demonstrated at the science awareness night at the Elitch Garden amusement park, attended by high school students and teachers. This amusement park has a broad appeal across ethnic groups and income levels, and reaches audiences underserved by more traditional outreach methods. These concepts will also be integrated in a short-term training workshop for secondary educators from local schools. Undergraduate students at the University of Denver will carry out parts of the proposal for their senior theses, for which they will be further trained in scientific writing and presentation skills. Results of the research, and codes developed to interpret experimental data will be made freely available online to the global protein science community. Besides immediate impact on protein science, the research will also impact design of new enzymes relevant in protein pharmaceuticals as well as biosynthesis of renewable energy carriers.
