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 .
