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: 6433092
• 负责人: JACOB 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/6433092
• 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. Z01 BC 08380-15

疾病及其治疗的基础在于对蛋白质、核酸和其他分子的三维结构的了解和理解。原子级结构的可用性、在理解其机制方面取得的进展以及我们开发的高效计算方法使我们能够研究受体分子表面上的结合位点，并将配体对接到受体表面，这将有助于设计有效的抑制剂。我们最近开发并继续改进分子表面的高效描述，这些表面描述已成功有效地用于对接从小药物到大分子大小的分子。使用我们的独立于序列顺序、基于计算机视觉的方法，内部和表面图案已被检测和编目。使用类似的工具，制作了蛋白质-蛋白质界面的数据集，并将其用于蛋白质关联的研究及其与蛋白质折叠的比较。该数据集与之前生成的蛋白质单体数据集的比较说明了界面和单链蛋白质的结构类型之间的相似性和差异。理论化学方法被纳入分析中，并表明界面中的亲水效应比疏水力更重要。一种高效的计算算法设计用于将蛋白质切割成高度疏水、紧凑的子域模块，用于生成折叠单元数据库，该数据库将提供对蛋白质结构及其组装方式的更深入了解。 RNA 的结构和功能与蛋白质一样重要，使用基于热力学的二级结构算法和分子力学和动力学进行三维预测建模。与诱变和核磁共振实验数据得出的相关性显示逆转录病毒核糖体移码的成功一致性。 5' 非翻译区 (5' URT) 中的内部核糖体进入是小核糖核酸病毒的标志，与保守的、预测的结构元件相关。在细胞 mRNA 的一些 5'UTR 中预测了类似的元件。预测方法不断完善。 Z01 BC 08380-15