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（由申请人提供）：许多大的生物分子含有高度灵活的结构成分，能够经历大规模的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。然而，通常情况下，含有高度灵活成分的大型复合物产生的晶体仅衍射至有限的分辨率（3~4.5¿）。因此，受相对较少数量的独特反射的限制，每个原子需要三个位置参数和六个热参数的全尺寸传统各向异性细化对于许多此类系统来说是不切实际的。因此，在最佳情况下，它们通常会针对每个原子使用一个各向同性 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反过来会恶化位置参数的细化，减慢整体收敛速度，并导致细化的结构模型产生较大误差。因此，在结构测定和功能研究中迫切需要新的方法来应对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很大影响，可以通过使用少量集体法线模式进行各向异性细化来减少这种误差。总体目标：我们的重点是开发新的模拟方法，以在结构测定和功能研究中更真实、更有效地表示生物分子的大规模变形。在此资助周期中，将开发一种新的基于法线模式的 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）算法和软件开发。将开发新的算法来提高 NM-XREF 的效率和准确性。此外，我们将投入大量精力将 NM-XREF 协议开发成用户友好的软件包，为整个结构生物学界服务。 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 的应用提供一般指南。 3) 细化选定的一组生物系统。我们选择了一些最具挑战性的生物系统，通过多次 NM-XREF 细化和手动调整进行更彻底的研究。最终的结构模型预计将为系统功能重要的动态提供新的见解。 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失的一些移动结构组件。我们广泛的初步结果表明，对于使用传统方法精修的大量有限分辨率结构，NM-XREF 对模型质量的改进仍然很大。此外，NMXREF 不仅优于 TLS 方法，而且在某些情况下依次使用它们时，还可以最大化 TLS 的增益。因此，将 NM-XREF 发展成为社区友好的工具是当务之急。 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，这通常涉及大规模的构象变形，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 射线细化协议，以更少的细化参数，在有限分辨率 (3~4.5¿) 的结构测定中提供更准确的构象变形描述。