MOLECULAR STRUCTURE OF ANIMAL VIRUSES AND CELLS BY COMPUTATIONAL ANALYSIS

通过计算分析动物病毒和细胞的分子结构

• 批准号: 6161012
• 负责人: J V MAIZEL
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6161012
• 关键词: Picornaviridae; Retroviridae; computer assisted sequence analysis; computer simulation; computer system design /evaluation; hydropathy; information systems; model design /development; nuclear magnetic resonance spectroscopy; nucleic acid sequence; protein folding; protein sequence; receptor binding; structural biology; virus DNA; virus RNA; virus genetics; virus protein

The basis of diseases and of their treatments resides in knowledge and comprehension of the three-dimensional structures of proteins, nucleic acids and other molecules. The availability of atomic-level structures, advances made in understanding their mechanisms, and highly efficient computational methodology that we have developed enables us to investigate binding sites on molecular surfaces of receptors, and to dock a ligand unto a receptor surface, which will be useful in the design of potent inhibitors. We have recently developed and continue to improve highly effective descriptions of molecular surfaces that are successfully and efficiently utilized for docking molecules ranging in size from small drugs to macromolecules. Using our sequence-order independent, computer-vision based methods, interior and surface motifs have been detected and catalogued. Using similar tools, a dataset of protein-protein interfaces was made and utilized for studies of protein associations and their comparison to protein folding. Comparisons of this dataset to a dataset of protein monomers, generated earlier, illustrates the similarities and differences between the types of architectures at interfaces and in single-chain proteins. Theoretical chemical methods are incorporated into the analyses and show that hydrophilic effects are more important than hydrophobic forces in interfaces. An efficient computational algorithm designed for cutting proteins into highly hydrophobic, compact, subdomain modules is used to produce a database of folding units that will provide deeper insights into the architecture of proteins and how they are assembled. RNA structure and function, no less important than that of proteins, is studied using thermodynamics-based algorithms for secondary structure and molecular mechanics and dynamics for three-dimensional predictive modelling. Correlations drawn with experimental data from mutagenesis and NMR show successful agreement in retroviral ribosomal frameshifting. Internal ribosome entry in 5' untranslated regions (5' URT), a hallmark of picornaviruses, correlates with conserved, predicted structural elements. Similar elements are predicted in some 5'UTR's of cellular mRNA's. Refinements in predictive methods are continually developed.

疾病及其治疗的基础在于知识， 理解蛋白质、核酸的三维结构 酸和其他分子。原子级结构的可用性， 在了解其机制方面取得了进展， 我们开发的计算方法使我们能够 研究受体分子表面的结合位点， 将配体对接到受体表面，这将在 设计有效的抑制剂。我们最近开发并继续 对分子表面改进的高效描述， 成功和有效地用于对接分子， 从小药物到大分子。使用我们的序列顺序 独立的，基于计算机视觉的方法，内部和表面图案 已经被发现并记录在案使用类似的工具， 制备了蛋白质-蛋白质界面，并用于蛋白质的研究 关联及其与蛋白质折叠的比较。比较 将这个数据集转换为蛋白质单体的数据集，之前生成的， 说明了不同类型的 在界面和单链蛋白质中的结构。理论 化学方法被纳入分析，并表明， 亲水作用比疏水力更重要， 接口。一种有效的切割计算算法 将蛋白质转化为高度疏水的、紧凑的亚结构域模块， 建立一个折叠单元数据库， 蛋白质的结构以及它们是如何组装的。 RNA的结构和功能与蛋白质一样重要， 使用基于几何学的二级结构算法进行研究 以及分子力学和动力学来预测 建模与突变实验数据的相关性 和NMR显示成功的协议在逆转录病毒核糖体移码。 5'非翻译区（5' URT）的内部核糖体进入， 小核糖核酸病毒，与保守的，预测的结构 元素在细胞的一些5 'UTR中预测了类似的元件， mRNA的。预测方法不断改进。