Development of Instrumentaton for Microcalorimetry of Biological Systems

该提案要求资金大幅提高用于研究生物系统的量热计的灵敏度。这种量热法的最终目标包括研究蛋白质-蛋白质和蛋白质-DNA相互作用的热力学，药物结合（蛋白质和DNA）的热力学和动力学，药物占用研究和蛋白质折叠的研究。Hellman博士使用基于半导体的微加工技术开发了微热量计，用于测量固态物理感兴趣的薄膜材料的比热。这些设备已成功地用于测量各种材料，厚度均小于5000 a，重量小于10kg；可以毫不夸张地说，在世界其他任何地方都无法进行这些测量。然而，迄今为止使用这些微量热计进行的所有测量都有一个要求：测量必须在真空中进行。这一要求是由于在气体或水蒸气中进行测量时，从样品区域到周围环境的过度热导会发生。然而，生物系统不能保持在真空中；它们通常是在会蒸发的水溶液中。对赫尔曼博士的工作提出的修改将允许在水蒸气饱和的氙气中使用，并将生产出比目前可能的测量灵敏度高得多的量热计。由于这些生物系统的数量很少，因此这项工作对目前方法无法获得的大分子的基础研究具有重要意义。

This proposal requests funds to dramatically increase the sensitivity of calorimeters used to study biological systems. The ultimate goals in this calorimetry includes the study of the thermodynamics of protein-protein and protein-DNA interactions, the thermodynamics and kinetics of drug binding (both proteins and DNA), drug occupancy studies, and studies of protein folding. Dr. Hellman has used semiconductor-based micromachining technology to develop microcalorimeters for measuring the specific heat of thin film materials of interest to solid state physics. These devices have been successfully used to measure a wide variety of materials, all less than 5000 A thick and weighing under 10 ,u g; it is not an exaggeration to say that these measurements could not be made anywhere else in the world. There is however one requirement to all the measurements made to date using these microcalorimeters: measurements must be made in vacuum. This requirement is due to the excess thermal conductance from the sample area to the surrounding environment which would occur if the measurements were attempted in a gas or in water vapor. Biological systems however cannot be held in vacuum; they are typically based in an aqueous solution which would evaporate. A proposed modification of Dr. Hellman's work will allow use in xenon saturated with water vapor and will produce calorimeters capable of much more sensitive measurements than is presently possible. Because many of these biological systems are only available in minute quantities, this work would be of great significance for basic research on macromolecules not accessible to present methods .