Isothermal titration calorimetry (ITC) is one of the most straightforward methods for characterizing the thermodynamics and stoichiometry of molecular interactions involving small molecules, proteins and polypeptides, antibodies, oligonucleotides, lipids and other biomolecules in aqueous solution. ITC is also used routinely for measuring metal ion binding to proteins, nanoparticle-biomolecule interactions, and metal ion-nanoparticle exchange. This is a 'label-free'approach, which simplifies sample preparation and allows the study of molecules in their native state (e.g., without need for fluorescence or radioisotopic labeling). Th GE/MicroCal iTC200 system is versatile, accurate and very sensitive, capable of measuring directly sub-millimolar to nanomolar binding constants~ stronger interactions can be investigated via competitive binding. Technical advances over the previous model enable this instrument to measure samples of roughly 7-fold lower volume (in a 200 mL cuvette), as well as at lower concentration (e.g., only 10 micrograms protein required). The rapid temperature equilibration time allows the iTC200 to analyze up to two samples per hour, while maintaining very high accuracy. This sample throughput is roughly twice that achieved with older ITC systems on UPenn's campus. In our field testing, MicroCal's iTC200 system produced high-quality, reproducible data on a variety of different samples. This ITC instrument has automated injection, syringe washing, and cuvette washing, which is useful for a multi-user instrument. The iTC200 will be a versatile analytical tool for this large users group, particularly enhanced by the greater speed, sensitivity and lower sample requirements of the iTC200 compared to older model ITC systems. We expect this instrument to be in high demand based on the large number of users who wanted to participate in this proposal as well as the high density of NIH-mission-driven biomedical research at University of Penn and the surrounding region. The new Director of the Biological Chemistry Service Center, Dr. Chris Lanci, will oversee day-to-day ITC operations, and will be in charge of keeping the instrument running optimally, training new users, and ensuring that the instrument receives frequent use by a large number of NIH-funded researchers. For the first two years of operation, the iTC200 will be free to all users, and we anticipate that ~ 30 user groups will become trained and collect ITC data during this time. An efficient management and cost-recovery scheme will keep the instrument delivering a high level of performance at reasonable cost to users for the next decade. At the time of installation, the proposed instrument will immediately benefit 16 user groups, ten of whom reside in the University Of Penn Department Of Chemistry and represent all four divisions (Organic, Inorganic, Biological, and Physical Chemistry). Also well represented is the University Of Penn School Of Medicine, with two Anesthesiology faculties and a member of the Institute of Environmental Medicine. Two University of Penn Bioengineering faculties and a member of the nearby Wistar Institute also have research needs for this versatile calorimeter.