COMPUTER ASSISTED MOLECULAR MODELING

缺乏结构性信息是 大多数蛋白质及其天然产物的特性 正在发生的变异。广达、洞察和Look等建模程序是 有助于通过以下方式在很大程度上克服上述问题 提供工具来生成这些三维结构 酶/受体。通过在Silicon Graphics上运行程序 在计算机上，我们开始研究各种膜的结构 实验室正在研究的受体和酶 神经遗传学。的跨膜螺旋区的结构 各种5-羟色胺受体是用电子产生的 以牛视紫红质密度图为模板结构。 含有16个或更少氨基酸的胞外和胞内环路 将被添加到这个螺旋结构中，以得到每个 5羟色胺受体。分子动力学分析，使用 Charmm和Dock计划将对这些结构进行 了解配基的特异性和结合。此外，同调 基于酵母转酮醇酶晶体结构的建模 执行硫胺素依赖酶：哺乳动物转酮醇酶和 丙酮酸脱氢酶复合体的e1-α和e1-β亚基，其 据报道，在几种神经退行性疾病中，活动减少。 观察到的各种自然发生的变种的结构 这些酶正在与当地的同类酶进行比较，以 描述某些变异氨基酸在结合蛋白中的作用 底物和辅因子以及酶催化。此外， 计算机辅助建模可用于表征其他 在NIAAA内部计划中正在进行研究的蛋白质。

Lack of structural information is a major stumbling block in the characterization of the majority of proteins and their naturally occurring variants. Modeling programs like Quanta, Insight and Look are useful in overcoming the above mentioned problems to a great extent by providing tools to generate three dimensional structures for these enzymes/receptors. By running the programs on the Silicon Graphics computer, we initiated to study the structures of various membrane receptors and enzymes that are being investigated in the Laboratory of Neurogenetics. Structures of the transmembrane helical domains of various serotonin receptors are being generated using the electron density map of bovine rhodopsin as the template structure. Extra-cellular and intra-cellular loops having 16 or less amino acids will be added to this helical structure to arrive at a model for each of the serotonin receptors. Analyses of molecular dynamics, using the programs Charmm and Dock, will be carried out on these structures to understand ligand specificity and binding. In addition, homology modeling based on the crystal structure of yeast transketolase has been performed for the thiamin dependent enzymes: mammalian transketolase and the E1-alpha and E1-beta subunit of pyruvate dehydrogenase complex, whose activities are reportedly reduced in several neurodegenerative diseases. The structures of the various naturally occurring variants observed in these enzymes are being compared to those of the native counterparts to delineate the roles of the certain variant amino acids in the binding of substrates and co-factors as well as enzyme catalysis. Furthermore, computer aided modeling can be utilized in the characterization of other proteins that are being investigated within the NIAAA Intramural Program.