Diseases are often the result of proteins that are malfunctioning. They may not be interacting with other molecules as they usually do. They might no longer perform their assigned function in a cell or tissue. Measuring the movements of individual proteins would help determine the exact nature of the problem causing the disease. However, capturing the rapid movements of single proteins is difficult. A single-protein manipulation technique will be employed to study the dynamic protein-protein interactions. A range of research-based, active-learning opportunities will be directed towards K-12 students and undergraduates. Underrepresented and disadvantaged students, as well as local Native Americans, will be actively recruited.<br/><br/>The goals of this project are to identify the dynamics of protein-ligand interactions and to attempt to manipulate these interactions relative to specific functions. A single-molecule manipulation approach will be developed. It will combine fluorescence assay methods with a high-speed, high-temporal resolution electronic single-molecule nanocircuit. The approach should allow the detection of subtle and transient conformational fluctuations and transitions. In addition, this project will probe ligand-dependent enzyme fluctuations, conformational transitions, and catalysis, and link them through protein-ligand binding models. Furthermore, this project aims to control enzyme functions by perturbing and stimulating enzyme activities during ligand interactions using a weak, non-thermal oscillating force field. Tuning the oscillation rate and the strength of the driving force may confirm the presence of stochastic resonance and stochastic activation in a driven nonlinear dynamic enzyme system. Once such activation is established, it could be used to trigger protein conformational dynamics and manipulate overall protein activities and functions.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.