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(申请人提供)：许多大的生物分子含有高度柔性的结构成分，它们经历了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，含有高度柔性组分的大型络合物产生的晶体只能衍射到有限的分辨率(3~4.5？)。因此，受相对较少的独特反射的限制，对于许多这样的系统来说，需要每个原子三个位置参数和六个热参数的全面的常规各向异性精化是不现实的。因此，在最好的情况下，它们通常是用每个原子的一个各向同性B因子来精炼的。不能以合理的精度模拟这些各向异性变形，反过来又恶化了位置参数的精化，减缓了整体收敛，并导致精化结构模型中的大误差。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：生物分子的大范围变形对结构确定的误差有很大贡献，这种误差可以通过使用少量集体简正模式的各向异性精化来减少。总体目标：我们的重点一直是开发新的模拟方法，以便在结构确定和功能研究中更真实和有效地表示生物分子的大范围变形。在这个资金周期中，将开发一种新的基于正常模式的X射线精细化协议(NM-XREF)，并在一大组有限分辨率结构中进行测试。具体目标：1)算法和软件开发。将寻求新的算法开发，以提高NM-XREF的效率和精度。此外，还将投入大量努力，将NM-XREF协议开发成一个用户友好的软件包，为整个结构生物学社区服务。2)NM-XREF的系统基准。我们将在50多个生物分子系统上系统地测试NM-XREF，并将其与TLS进行比较。研究结果可望为NM-XREF的应用提供一般指南。3)精选一组生物系统。我们选择了一些最具挑战性的生物系统，通过多个周期的NM-XREF改进和手动调整进行了更彻底的研究。最终的结构模型预计将为系统的重要功能动态提供新的见解。4)哺乳动物脂肪酸合成酶的结构测定。通过使用NM-XREF，我们希望解决以前研究中缺失的一些移动结构部件。我们广泛的初步结果表明，对于大量用常规方法精化的有限分辨率结构，NM-XREF对模型质量的改善仍然是相当可观的。此外，NMXREF不仅在性能上优于TLS方法，而且在某些情况下，当它们被顺序使用时，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。 生物分子的原子结构对于理解它们的细胞功能是至关重要的，这通常涉及大规模的构象变形，特别是对于大的蛋白质组装。虽然这些大范围的形变在功能上很重要，但却给X射线结晶学中的结构细化带来了巨大的困难。这一建议旨在开发一种新的X射线精化方案，该方案以较少的精化参数，在有限的分辨率(3~4.5？)下更准确地描述结构确定中的构象变形。