| Co-Investigator(Kenkyū-buntansha) |
KAJIYAMA Koichi Adomon Science, Inc., CEO, 社長
TOMIYAMA Tetsuo Faculty of Sci., Nagoya Univ., Res. Assoc., 理学研究科, 助手 (20155576)
YOSHIDA Takuya School of Pharm. Sci., Osaka University Res. Assoc., 薬学研究科, 助手 (00294116)
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| Budget Amount *help |
¥8,000,000 (Direct Cost: ¥8,000,000)
Fiscal Year 1999: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 1998: ¥6,300,000 (Direct Cost: ¥6,300,000)
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| Research Abstract |
A major biological function of many proteins is the binding of small molecules. For examples, enzymes bind substrates and effector molecules, and transport proteins such as hemoglobin or storage proteins such as myoglobin bind oxygen. Almost all biological functions involve the interactions of those small molecules that serve as metabolites, regulators, and signals with the specific surfaces of the proteins that carry out cellular processes. For this reason, an understanding of the mechanisms of such interactions is essential to a comprehension of biological process at the molecular level. In most cases, such binding involves the formation of some kind of noncovalent bond between the small molecules called as ligand and some specific region on or near the surface of the protein called as the binding site. The protein-lgand complexes are in thermodynamic equilibrium with their dissociated components, and in many cases it is possible to measure the thermodynamic parameters for these reac
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tions.
Fundamental thermodynamic relationships reveal that volumetric studies on molecules of interest can yield useful new information. The intrinsic volume, Vm, (the geometric volume of a solute not accessible to surrounding solvent molecules) and the intrinsic compressibility, Km, (compressibility of the solvent-inaccessible protein core) of a protein-ligand complex reflect the intrinsic packing of the constituent and are detemined by intermolecular interactions within the solvent-inaccessible protein interior. Consequently, any changes in protein structure induced by ligand binding should be reflected in the values of Vm and Km.
In this research project, the properties of protein-ligand complex as a function of solution conditions, including the role of solvation have been characterized by volumetric studies. Until recently, such studies on biologically interesting molecules have been limited because of the lack of readily available instrumentation with the requisite sensitivity. We have improved the instruments and constructed a highly sensitive, small-volume densimetric, acoustic and high-pressure spectroscopic instrumentation which enabled biological molecules to be subjected to a wide range of volumetric studies. Using these instruments, we have obtained unique insights into the molecular origins of the intermolecular recognition events that modulate biomolecular processes. Less
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