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: 2463735
• 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/2463735
• 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 the proteins, nucleic acids and other molecules which are involved. The availability of atomic-level structures, advances made in understanding their mechanisms, and highly efficient computational methodology which 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 successful and efficiently utilized for docking molecules of variable sizes. 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 the 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， 对蛋白质三维结构的理解， 核酸和其他相关分子。的可用性 原子级结构，在理解它们的过程中取得的进展， 机制和高效的计算方法，我们 使我们能够研究分子上的结合位点， 受体表面，并将配体对接到受体表面， 这将有助于设计有效的抑制剂。我们有 最近开发并不断改进， 成功有效的分子表面的描述 用于对接可变大小的分子。使用我们 序列顺序独立，基于计算机视觉的方法，内部和 表面图案已被检测并编目。使用类似的工具， 制作了蛋白质-蛋白质界面的数据集，并用于 蛋白质缔合及其与蛋白质的比较研究 折页.该数据集与蛋白质单体数据集的比较 之前生成的，说明了之间的相似性和差异 接口处和单链中的架构类型 proteins.理论化学方法被纳入到 分析表明，亲水效应比 界面中的疏水力。一种有效的计算算法 设计用于将蛋白质切割成高度疏水的，紧凑的， 子域模块用于产生折叠单元的数据库， 将提供更深入的了解蛋白质的结构， 他们被集合起来。 RNA的结构和功能，其重要性不亚于蛋白质， 是研究使用基于几何学的算法，为二次 三维结构和分子力学与动力学 预测建模与实验数据得出的相关性 诱变和NMR显示在逆转录病毒核糖体中成功一致 移码5 '非翻译区的内部核糖体进入 （5 'URT），小核糖核酸病毒的标志，与保守的， 预测的结构要素。类似的元素预测在一些 细胞mRNA的5 'UTR。预测方法的改进包括 不断发展。