New Simulation Methods at Multi-Scale and -Resolutions

描述(申请人提供)：许多生物分子，特别是大的复合体，是高度灵活和动态的。尽管这些分子在功能上很重要，但许多分子的大柔性通常表示为各向异性变形，不能用常规方法进行充分的研究。简正波分析是描述生物分子大尺度各向异性变形的有效方法，但是当感兴趣体系的规模和变形的规模越来越大时，简正波分析存在着巨大的困难。因此，迫切需要新的计算程序来高精度地捕捉结构和功能研究中的大尺度各向异性变形。在当前的资助周期中，PI的团队已经成功地开发了基于正常模式的X射线细化协议(NM-XREF)，以改进具有大规模各向异性变形的生物分子的结构细化。在下一个资金周期，PI的目标是开发一系列不同的新计算技术，用于对大型蛋白质变形进行多尺度(从粗粒度到原子尺度)建模。这些新方法与NM-XREF的结合使用有望极大地提高其在重大生物系统结构优化方面的效率。假设：具有重要功能的生物分子的大范围变形通常是各向异性的，这可以用低频简正波来最好地逼近。功能强大的新的多尺度简正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研究。长期目标：重点一直是开发新的模拟方法，以更真实和有效地表示结构和功能研究中生物分子的大规模变形。具体目标：1)提出一种用于超大型系统振动分析的新的模态综合法。2)设计了一种新的晶体环境下简正模式分析算法。3)统一简正振型分析和平移-振动-螺旋方法的基组。4)生成一种新的用于X射线建模的各向异性锐化方案。此外，这些新方法将被用来改进特定类别的X射线结构的精细化，这些结构在结构研究中各自提出了自己的挑战。总的来说，一系列用于功能和结构研究的新的多尺度计算方法的实施有望极大地造福于整个科学界。

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.