This award supports a three year collaborative research project between Professor Gregory Petsko of Brandeis University and Professor Tairo Oshima of the Tokyo University of Pharmacy and Life Science in Japan. The researchers will be undertaking a study of the interrelationship of protein flexibility, activity and thermal stability. Proteins are highly flexible molecules, but the role, if any, of this flexibility in their biological activity and structural stability is still an open question. Industrial and medical uses of proteins require molecules that retain activity over a wide range of temperatures, but the rules governing stability at high temperatures are not well understood. The aim of this collaboration is to determine the interrelationship between protein flexibility, catalytic activity and thermal stability. The model system to be used is 3-isopropylmalate dehydrogenase from several organisms (Thermus thermophilus, Escherichia coli, Samonella typhimurium, and Vibrio sp.15). A series of experiments combining genetic selection, X-ray crystallography, kinetic analysis and the mapping of protein flexibility by the analysis of B-factors have been designed to provide data relating these properties.
This project brings together the efforts of two laboratories that have complementary expertise and research capabilities. Results of this research should reveal the basic principles that describe how the dynamic behavior of an enzyme contributes to catalytic efficiency and how flexibility in a protein structure affects the temperature at which that protein unfolds. From these principles it should be possible to design improved temperature stability into mesophilic (human) proteins without crippling their activity. This research advances international human resources through the participation of graduate students. Through the exchange of ideas and technology, this project will broaden our base of basic knowledge and promote international understanding and cooperation. ***
