New Simulation Methods at Multi-Scale and -Resolutions

描述（由申请人提供）：许多生物分子，特别是大型复合物，具有高度的灵活性和动态性。尽管这些分子在功能上很重要，但它们中的许多分子的大柔韧性（通常表示为各向异性变形）无法用传统方法进行充分研究。正态模态分析是描述生物分子大尺度各向异性变形的有效方法，但随着研究对象的规模和变形规模的增大，正态模态分析存在极大的困难。因此，迫切需要新的计算程序来高精度地捕获结构和功能研究的大尺度各向异性变形。在当前的资助周期中，PI的团队已经成功开发了一种基于正常模式的x射线细化方案（NM-XREF），以改善具有大规模各向异性变形的生物分子的结构细化。对于下一个资助周期，PI的目标是开发各种各样的新计算技术，用于大蛋白质变形的多尺度（从粗粒度到原子尺度）建模。这些新方法与NM-XREF的耦合使用有望大大提高其在重要生物系统结构精化中的效率。假设：具有重要功能的生物分子的大规模变形通常是各向异性的，这可以用低频正态模式最好地近似。强大的新多尺度正态分析算法可以更准确地描述这种变形，将允许更有效的结构和功能研究。长期目标：重点是开发新的模拟方法，以在结构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。具体目标：1)开发一种新的模态综合方法用于超大型系统的模态分析。2)设计一种新的晶体环境下的正态分析算法。3)统一正态分析和平移-振动-螺旋法的基集。4)生成一种新的用于x射线模型构建的各向异性锐化方案。此外，这些新方法将用于改进特定类别的x射线结构，每种x射线结构在结构研究中都有自己的挑战。总之，一系列用于功能和结构研究的新型多尺度计算方法的实施有望极大地造福整个科学界。

DESCRIPTION (provided by applicant): Many biological molecules, especially large complexes, are highly flexible and dynamic. Although functionally important, large flexibility of many of these molecules, frequently expressed as anisotropic deformations, cannot be adequately studied using conventional means. Normal mode analysis is an effective way for describing large-scale anisotropic deformations of biomolecules, however, there exist tremendous difficulties when the size of systems of interest and the scale of deformations are getting increasingly larger. Therefore, there is a pressing need for new computational procedures to capture, with high accuracy, the large-scale anisotropic deformations for structural and functional studies. In the current funding cycle, the PI's group has successfully developed a normal-mode-based X-ray refinement protocol (NM-XREF) to improve structural refinement of biomolecules with large-scale anisotropic deformations. For the next funding cycle, the PI aims to develop a diverse array of new computational techniques for multi-scale (from coarse-grained to atomic scale) modeling of large protein deformations. The coupled use of these new methods with NM-XREF is expected to greatly enhance its efficiency in structural refinement of significant biological systems. Hypotheses: Large-scale deformations of biomolecules of functional importance are frequently anisotropic, which can be best approximated by low-frequency normal modes. Powerful new multi-scale normal mode analysis algorithms that can more accurately describe such deformations will allow more efficient structural and functional studies. Long-term Objectives: The focus has been on developing new simulation methods to represent more realistically and efficiently large-scale deformations of biomolecules in structural and functional studies. Specific Aims: 1) To develop a new modal synthesis method for mode analysis of extremely large systems. 2) To design a new algorithm for normal mode analysis in crystalline environment. 3) To unify the basis sets of normal mode analysis and Translation-Libration-Screw method. 4) To generate a new anisotropic sharpening scheme for X-ray model building. Furthermore, these new methods will be used to improve refinement of specific classes of X-ray structures that each presents its own challenges in structural study. Collectively, the implementation of a series of novel multi-scale computational methods for functional and structural study is expected to greatly benefit the entire scientific community. PUBLIC HEALTH RELEVANCE: Many biological molecules, especially large complexes, are highly flexible and dynamic. Although functionally important, large flexibility of many of these molecules, frequently expressed as anisotropic deformations, cannot be adequately studied using conventional means. This proposal aims to develop a diverse array of new computational techniques for high-accuracy modeling of large-scale protein deformations and for enhancing structural refinement of significant biological systems, thus is highly relevant to public health.