Molecular Structure of Animal Viruses and Cells by Compu

用计算机分析动物病毒和细胞的分子结构

• 批准号: 6559002
• 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/6559002
• 关键词: computer simulation; molecular dynamics; nuclear magnetic resonance spectroscopy; nucleic acid structure; protein folding; protein structure; receptor binding; structural biology; virus RNA; virus morphology; 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三维结构的认识和理解， 核酸和其他分子。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，这些分子表面成功且有效地用于对接大小不等的分子 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，内部和表面图案已被检测和编目。使用类似的工具，蛋白质-蛋白质界面的数据集被制作并用于蛋白质缔合的研究及其与蛋白质折叠的比较。将该数据集与之前生成的蛋白质单体数据集进行比较，说明了界面处和单链蛋白质中结构类型之间的相似性和差异。理论化学方法被纳入到分析中，并表明，亲水性的影响是更重要的比疏水力的接口。设计用于将蛋白质切割成高度疏水、紧凑的子域模块的高效计算算法用于产生折叠单元的数据库，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，不亚于蛋白质的重要性，研究使用基于几何学的算法的二级结构和分子力学和动力学的三维预测建模。从诱变和核磁共振实验数据得出的相关性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）的内部核糖体进入是小核糖核酸病毒的标志，与保守的预测结构元件相关。在细胞mRNA的一些5 'UTR中预测了类似的元件。预测方法不断改进。 Z01 BC 08380-15