New Simulation Methods at Multi-Scale and -Resolutions

多尺度和分辨率的新模拟方法

• 批准号: 7526221
• 负责人: JIANPENG MA
• 金额: $ 27.63万
• 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/7526221
• 关键词: Benchmarking; Biological; Cell physiology; Cereals; Classification; 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; Numbers; Outcome; Pliability; Proteins; Protocols documentation; Public Health; Range; Research; Resolution; Roentgen Rays; Solid; Structural Models; Structure; System; Temperature; Testing; X-Ray Crystallography; base; caN protocol; coping; density; experience; improved; insight; molecular mass; protein structure; 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（由适用提供）：许多大型生物分子都包含高度柔性的结构组件，这些结构成分经历了大规模各向异性和集体变形。理想情况下，应使用各向异性温度B因子更准确地描述这些变形。但是，很常见的大型复合物包含高度柔韧的成分产生的晶体，这些晶体仅衍射为有限的分辨率（3〜4.5€）。受到相对较少数量的独特反射的限制，对于许多这样的系统而言，每种原子需要三个位置和六个热参数的全尺度传统各向异性细化是不切实际的。结果，在最佳情况下，它们通常会为每个原子使用一个各向同性B因子进行完善。无法以合理精度对这些各向异性变形进行建模，从而决定了位置参数的完善，减慢了整体收敛性，并导致精制结构模型的误差很大。因此，迫切需要新的方法来应对结构确定和功能研究中蛋白质结构的大变形。假设：生物分子的大规模变形对结构确定的误差有显着贡献，可以使用少量的集体正常模式来通过各向异性细化来降低。一般目标：我们的重点一直在开发新的仿真方法上，以在结构确定和功能研究中更真实有效地表示生物分子的大规模变形。在这个融资周期中，将开发和测试一种新的基于正常模式的X射线改进协议（NM-XREF），并在一系列限量分辨率结构中进行测试。具体目的：1）算法和软件开发。将追求新的算法开发，以提高NM-XREF的效率和准确性。此外，将投入大量努力将NM-XREF协议开发到一个用户友好的软件包中，以服务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50多个生物分子系统上的TLS进行比较。预计结果将为NM-XREF的应用提供一般指南。 3）精选的一组生物系统。我们已经选择了一些最挑战的生物系统，以通过多个NM-XREF细化和手动调整进行多个循环进行更彻底的研究。最终的结构模型有望为系统的功能动力学提供新的见解。 4）哺乳动物脂肪酸合酶的结构测定。通过使用NM-XREF，我们希望解决以前研究中缺少的一些移动结构组件。我们广泛的初步结果表明，对于使用常规方法完善的大量限量结构，NM-XREF的模型质量提高仍然是次要的。此外，NMXREF不仅胜过TLS方法，而且在某些情况下依次使用TLS时，TLS的增益最大化。这是，将NM-XREF发展成为社区友好工具是一个很高的优先事项。 生物分子的公共卫生相关性原子结构对于理解其细胞功能至关重要，该结构通常涉及大规模构象变形，特别是对于大蛋白质组件。尽管在功能上很重要，但这些大规模的变形在X射线晶体学的结构改进方面造成了增强的困难。该建议旨在开发一种新的X射线改进协议，该协议较少，而细化参数较少，可以更准确地描述有限分辨率下结构确定中的构象变形（3-4.5€）。