CAREER - Flexibility vs. Preorganization: Atomistic Simulations of Partner Recognition by Natively Unfolded Peptides

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A substantial fraction of proteins are natively unfolded, or lack well-defined structure. Many of these proteins fold only upon binding to their partner proteins, suggesting a new paradigm for protein-protein recognition. This new paradigm challenges the conventional assumption that proteins bind their partners more quickly if they are preorganized, adopting structures in their unbound states that are identical to structures in their bound states. This CAREER project will reassess this assumption by comparing the rates of partner-binding by natively unfolded peptides with their exact, preorganized analogues using atomically detailed computer simulations. Such direct comparison is not achievable by laboratory experiments. Novel aspects of this research are (a) the use of the weighted ensemble approach to focus atomistic computer simulations on the sampling of rare binding events that involve conformational changes, or changes in the shapes of the binding partners, (b) its implementation within distributed computing resources to dramatically increase the methodology's computational reach, and (c) the intention to study realistic binding rates without forcing the events to occur. Results from this project will advance the understanding of fundamental principles governing molecular recognition and could therefore improve strategies for designing highly specific inhibitors of chosen protein-protein interactions, molecular sensors, and molecular switches.Broader Impacts. With the increasingly interdisciplinary nature of modern research, it is essential for students to learn how to give effective scientific presentations to broad audiences. Dr. Chong has designed and taught an undergraduate course that helps students develop effective scientific presentations through intensive practice and feedback throughout the semester. Building on this experience, she will develop additional approaches for helping students improve their speaking skills. These approaches include training students to communicate specific concepts in science within five minutes and packaging these presentations into podcasts and digital videos. To broaden the outreach of this training, Dr. Chong will encourage undergraduates from institutions all over the country to create such videos in a contest that she will organize at a national conference. Goals of this contest include: a) to help undergraduates develop effective communication skills and b) to promote interest in the sciences among undergraduates, including minorities. Finally, Dr. Chong will extend the training to graduate students by designing a graduate course in giving effective scientific presentations.