IDBR: Development of Ultrasensitive, Superfast, and Microliter-Volume Differential Scanning Nanocalorimeter for Direct Characterization of Biomolecular Interactions

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Award Abstract: Development of Ultrasensitive, Superfast, and Microliter-Volume Differential Scanning Nanocalorimeter for Direct Characterization of Biomolecular InteractionsThe proposed differential scanning nanocalorimeter will significantly reduce the sample volume and shorten the measurement time of molecular phenomena, and provide a powerful tool for comprehensive high-content thermodynamics studies, in the study of membrane proteins and in the early stage of drug discovery. This multidisciplinary research will provide excellent opportunities to young scientists and engineers, especially women and underrepresented minorities. Interaction with national laboratories and industry at different ends of the application spectrum will enable accelerated implementation of the developed knowledge.All biological phenomena depend on molecular interactions, which is either intermolecular, as with ligand binding to a protein, or intramolecular, as with protein folding. As a label-free and immobilization-free method, modern calorimetry instrumentation is the gold standard for directly characterizing the thermodynamic profiles of molecular interactions, including Gibbs free energy, enthalpy, entropy, specific heat, and stoichiometry, providing valuable information for investigating biolomolecular mechanisms and drug design, information that cannot be obtained from structural or computational methods alone. However, the current state-of-the-art calorimeters require large-volume, high-concentration proteins and need very long measurement times, which limits their utility for biological studies. The objective of this award is to develop an innovative MEMS-based differential scanning nanocalorimeter and array to reduce the consumption of biological macromolecules from milliliters to micro liters, and to decrease the measurement time from hours to minutes, and thus enable direct, precise, and rapid detection of biomolecular interactions. To achieve this goal, four specific tasks are planned, including 1) designing and fabricating ultrasensitive low-noise sensors, 2) minimizing the parasitic heat loss of the nanocalorimeter, 3) designing and integrating low-noise electronics and feedback controller, and 4) testing and applying this technology to membrane protein study and pharmaceutical screening.