COMPUTER ASSISTED MOLECULAR MODELING

缺乏结构信息是一个主要的绊脚石， 大多数蛋白质及其天然产物的特性 发生变异。 Quanta、Insight和Look等建模程序 在很大程度上可用于克服上述问题， 提供生成三维结构的工具。 我们有 开始研究各种膜受体的结构， 正在研究基因功能变异的酶， 神经遗传学实验室 跨膜螺旋的结构 各种血清素受体的结构域正在使用 以牛视紫红质为模板结构的电子密度图。 具有16个或更少氨基酸的细胞外和细胞内环 将被添加到这个螺旋结构，以达到每个模型， 血清素受体 分子动力学分析，使用 将在这些结构上进行Charmm和Dock程序， 了解配体特异性和结合。 此外，同源性 基于酵母转酮醇酶晶体结构的建模已经被 进行硫胺素依赖性酶，哺乳动物转酮醇酶和 丙酮酸脱氢酶复合物E1 α和E1 β亚基，其 据报道，活性在几种神经变性疾病中降低。 观察到的各种天然存在的变体的结构， 这些酶与天然对应物的酶进行比较， 描述了某些变体氨基酸在结合 底物和辅因子以及酶催化。 此外，委员会认为， 计算机辅助建模可以用于表征其他 NIAAA正在研究的蛋白质。

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. We have initiated study on the structures of various membrane receptors and enzymes that are being investigated for genetic functional variation 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 E1alpha and E1beta 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 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 by the NIAAA.