New Simulation Methods at Multi-Scale and -Resolutions

多尺度和分辨率的新模拟方法

• 批准号: 8113159
• 负责人: JIANPENG MA
• 金额: $ 27.08万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113159
• 关键词: Benchmarking; Biological; Cell physiology; Cereals; Communities; Complement Factor B; Complex; Computer Simulation; Computing Methodologies; Data; Deterioration; Development; Docking; Effectiveness; Family suidae; Fatty-acid synthase; Foundations; Frequencies; Funding; Goals; Grouping; Guidelines; Investigation; Location; Manuals; Maps; Methodology; Methods; Modeling; Motion; Outcome; Protein Dynamics; Proteins; Protocols documentation; Research; Resolution; Roentgen Rays; Solid; Structural Models; Structure; System; Temperature; Testing; X-Ray Crystallography; base; biological systems; coping; density; experience; flexibility; improved; insight; molecular mass; protein structure; public health relevance; simulation; software development; structural biology; tool; user friendly software; user-friendly

DESCRIPTION (provided by applicant): Many large biomolecules contain highly flexible structural components that undergo large-scale anisotropic and collective deformations. Ideally, these deformations should be more accurately described using anisotropic temperature B-factors. However, very frequently, large complexes containing highly flexible components yield crystals that only diffract to limited resolutions (3~4.5¿). Thus, limited by the relatively small number of unique reflections, a full-scale conventional anisotropic refinement that requires three positional and six thermal parameters for each atom is impractical for many such systems. As a result, they are often refined with one isotropic B-factor for each atom at the best scenario. The inability to model these anisotropic deformations with reasonable accuracy in turn deteriorates the refinement of positional parameters, slows down the overall convergence, and results in large errors in refined structural models. Therefore, new methods are urgently needed to cope with large deformations of protein structures in structure determination and functional study. Hypotheses: Large-scale deformations of biomolecules contribute significantly to the errors in structure determination, which can be reduced by anisotropic refinement using a small number of collective normal modes. General Objectives: Our focus has been on developing new simulation methods to represent more realistically and efficiently large-scale deformations of biomolecules in structure determination and functional study. In this funding cycle, a new normal-mode-based X-ray refinement protocol (NM-XREF) will be developed and tested in a large set of limited-resolution structures. Specific Aims: 1) Algorithmic and software development. New algorithmic development will be pursued to improve the efficiency and accuracy of NM-XREF. Furthermore, substantial efforts will be invested to develop the NM-XREF protocol into a user-friendly software package for serving the entire structural biology community. 2) Systematic benchmark of NM-XREF. We will systematically test NM-XREF and compare it with TLS on over 50 biomolecular systems. The outcome is expected to provide a general guideline for the application of NM-XREF. 3) Refinement of a selected group of biological systems. We have selected some of the most challenging biological systems for a more thorough investigation through multiple cycles of NM-XREF refinement and manual adjustment. The final structural models are expected to provide new insights into the functionally important dynamics of the systems. 4) Structure determination of mammalian fatty acid synthase. By using NM-XREF, we hope to resolve some of the mobile structural components missing in previous studies. Our extensive preliminary results suggest that, for a large number of limited-resolution structures refined using conventional methods, the improvement of model quality by NM-XREF is still substantial. Moreover, NMXREF not only outperforms the TLS method, but also maximizes the gain by TLS when they are sequentially utilized in some cases. Thus, it is of a high priority to develop NM-XREF into a friendly tool for the community. PUBLIC HEALTH RELEVANCE Atomic structures of biomolecules are critical to the understanding of their cellular functions, which often involve large-scale conformational deformations, especially for large protein assemblies. Although functionally important, those large-scale deformations impose enormous difficulties on structural refinement in X-ray crystallography. This proposal aims to develop a new X-ray refinement protocol that, with fewer refinement parameters, provides a more accurate description of conformational deformations in structure determination at limited resolutions (3~4.5¿).

描述（由申请人提供）：许多大生物分子含有高度柔性的结构组分，其经历大规模各向异性和集体变形。理想情况下，这些变形应该使用各向异性温度B因子更准确地描述。然而，非常常见的是，含有高度柔性组分的大络合物产生的晶体只能在有限的分辨率（3~4.5 <$）下起作用。因此，受限于相对少量的独特反射，对于许多这样的系统，需要每个原子的三个位置参数和六个热参数的全尺寸常规各向异性细化是不切实际的。因此，在最佳情况下，它们通常用每个原子的一个各向同性B因子进行细化。无法以合理的精度对这些各向异性变形进行建模，进而恶化了位置参数的细化，减慢了整体收敛，并导致细化结构模型中的大误差。因此，在蛋白质结构测定和功能研究中，迫切需要新的方法来科普蛋白质结构的大变形。假设：生物分子的大规模变形对结构测定中的误差有很大的贡献，这可以通过使用少量的集体简正模的各向异性细化来减少。总体目标：我们的重点是开发新的模拟方法，以更真实，更有效地代表生物分子的结构测定和功能研究的大规模变形。在这个资金周期中，将开发一种新的基于正常模式的X射线细化协议（NM-XREF），并在大量有限分辨率结构中进行测试。具体目标：1）计算机和软件开发。新的算法开发将继续进行，以提高NM-XREF的效率和准确性。此外，将投入大量精力将NM-XREF协议开发成用户友好的软件包，以服务于整个结构生物学社区。2)NM-XREF的系统基准。我们将系统地测试NM-XREF，并将其与TLS在50多个生物分子系统上进行比较。该结果有望为NM-XREF的应用提供一般性指导。3)一组选定的生物系统的改进。我们选择了一些最具挑战性的生物系统，通过多个周期的NM-XREF优化和手动调整进行更彻底的调查。最后的结构模型预计将提供新的见解功能重要的动态系统。4)哺乳动物脂肪酸合成酶的结构测定。通过使用NM-XREF，我们希望解决一些移动的结构组件在以前的研究中丢失。我们广泛的初步结果表明，对于大量的有限分辨率的结构，使用传统的方法，改进模型质量的NM-XREF仍然是巨大的。此外，NMXREF不仅优于TLS方法，而且在某些情况下顺序使用TLS时可以最大化TLS的增益。因此，将NM-XREF开发成为社区的友好工具是一个高度优先事项。 公共卫生相关性生物分子的原子结构对于理解其细胞功能至关重要，这通常涉及大规模构象变形，特别是对于大型蛋白质组装体。尽管在功能上很重要，但这些大规模变形给X射线晶体学中的结构细化带来了巨大的困难。该提案旨在开发一种新的X射线细化方案，该方案使用较少的细化参数，在有限分辨率（3~4.5 <$）下提供结构测定中构象变形的更准确描述。