New Simulation Methods at Multi-Scale and -Resolutions

描述（由申请人提供）：许多生物分子，特别是大的复合物，是高度灵活和动态的。虽然功能重要，大的灵活性，这些分子中的许多，经常表示为各向异性变形，不能充分研究使用常规手段。简正模分析是描述生物分子大尺度各向异性形变的有效方法，但当系统尺寸和形变尺度越来越大时，简正模分析存在着巨大的困难。因此，迫切需要新的计算程序来捕获，高精度，大规模的各向异性变形的结构和功能的研究。在当前的资金周期中，PI的团队成功开发了一种基于正常模式的X射线细化协议（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。在下一个资助周期，PI的目标是开发一系列新的计算技术，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的结合使用有望大大提高其在重要生物系统结构优化中的效率。假设：具有重要功能的生物分子的大尺度变形通常是各向异性的，这可以通过低频简正模式来最好地近似。强大的新的多尺度正常模式分析算法，可以更准确地描述这种变形将允许更有效的结构和功能的研究。长期目标：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和功能研究的大规模变形。具体目标：1）发展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简正波分析算法。3)统一简正模态分析和平动-平动-旋量法的基组。4)提出一种新的各向异性锐化方案用于X射线模型的建立。此外，这些新方法将用于改进特定类别的X射线结构的细化，每种结构在结构研究中都提出了自己的挑战。总的来说，一系列新的多尺度计算方法的功能和结构研究的实施，预计将大大有利于整个科学界。

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.