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タンパク質立体構造の安定性・ダイナミックス・折れたたみ機構

蛋白质3D结构的稳定性、动力学和折叠机制

基本信息

批准号：
07280103
负责人：
YUTANI Katsuhide
金额：
$ 156.29万
依托单位：
OSAKA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1998
项目状态：
已结题

项目摘要

In order to analyze "principles of protein architecture", that is, the principle of how protein three-dimensional structures are coded for in their amino acid sequence, we have studied physico-chemical aspects of protein conformation. To do it there are two major groups : (1) a thorough study of a model protein, human lysozyme and (2) a study of important projects on protein stability, protein dynamics, and protein folding. As to the first project (Yutani, Yamagata, and Kitao), more than 100 mutant human lysozymes with systematic and comprehensive substitutions are constructed. Changes in stabilities and structures due to mutations were examined by calorimetry and X-ray analysis, respectively. On the basis of the obtained stability-structure data-base, the relationship between changes in stability and structure due to mutations was examined and each parameter of stabilization factors could be successfully estimated after due consideration on such as secondary structure propensity, introduction of water, formation and removal of hydrogen bond, differences in accessible surface area of polar and non-polar atoms due to denaturation. These results indicate that (1) non-polar atoms play an important role in protein stability but polar atoms do not, (2) if a hydrogen bond in which the length is 3 A is removed due to substitution, the mutant protein should be destabilized by 8.6 kJ/mol, (3) when one water molecule is newly introduced in the interior of a protein, it is destabilized by 7.2 kJ/mol due to entropic effect. As to the second project, Kidokoro and Yutani studied stability of proteins from thermophile. Kushide developed time-resolved hole-burning spectroscopy by himself and examined conformational fluctuations and dynamics of Zn-substituted myoglobin. Kidera, Kataoka, Kuwajima, and Goto studied important problems of dynamics, protein folding, and non-native structures of a protein. Kumagai and Kidokoro also studied important problems of protein function.

为了分析“蛋白质结构原理”，即蛋白质三维结构如何在其氨基酸序列中编码的原理，我们研究了蛋白质构象的物理化学方面。要做到这一点，有两个主要群体：（1）一个模型蛋白质，人类溶菌酶的彻底研究和（2）蛋白质稳定性，蛋白质动力学和蛋白质折叠的重要项目的研究。关于第一个项目（Yutani，Yamagata和Kitao），构建了100多个具有系统和全面替换的突变体人溶菌酶。通过量热法和X-射线分析，分别检查由于突变的稳定性和结构的变化。在获得的稳定性结构数据库的基础上，由于突变的稳定性和结构的变化之间的关系进行了检查，并在适当考虑如二级结构倾向，水的引入，氢键的形成和去除，由于变性的极性和非极性原子的可及表面积的差异后，可以成功地估计稳定化因子的每个参数。这些结果表明（1）非极性原子在蛋白质稳定性中起重要作用，但极性原子不起重要作用，（2）如果由于取代而去除长度为3的氢键，则突变蛋白质应被8.6kJ/mol去稳定化，（3）当在蛋白质内部新引入一个水分子时，由于熵效应，它被7.2kJ/mol去稳定化。关于第二个项目，Kidokoro和Yutani研究了嗜热菌蛋白质的稳定性。Kushide自行开发了时间分辨烧孔光谱，并研究了Zn取代肌红蛋白的构象波动和动力学。Kidera，Kataoka，Joshima和后藤研究了动力学，蛋白质折叠和蛋白质非天然结构的重要问题。Kumagai和Kidokoro还研究了蛋白质功能的重要问题。