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INSPIRE: Assessing feasible regions of configuration spaces for macromolecular crystals

INSPIRE：评估大分子晶体构型空间的可行区域

基本信息

批准号：
1640970
负责人：
Gregory Chirikjian
金额：
$ 60万
依托单位：
Johns Hopkins University
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1640970&HistoricalAwards=false
关键词：
INSPIRE Assessing feasible regions configuration

项目摘要

This INSPIRE project is jointly funded by Algorithmic Foundations in CISE/CCF, Analysis in MPS/DMS, and the NSF Office of Integrative Activities.Knowledge of the 3-dimensional structure of protein molecules supports scientific understanding of how proteins perform their functions within cells. Structures of over 100,000 proteins in the Protein Data Bank have been determined by macromolecular x-ray crystallography: measuring the diffraction of x-ray beams from crystal composed of many symmetrically arranged copies of one or more protein molecules gives partial information (the amplitudes of the Fourier transform) that must be filled in (solving the "phase problem," often by molecular replacement -- taking phases from related molecules) to complete the 3d structure. Molecular replacement works quite well for simple single-domain proteins, but breaks down for multi-domain proteins and large complexes; one needs to explore the possible combinations of domains and their diffraction patterns as replacement candidates. This cross-disciplinary project brings together experts in robotics and in pure mathematics to address the ''phase problem'' of macromolecular x-ray crystallography. The mathematical and computational framework developed in this project will enable many more protein structures to be solved in a less laborious way than can be done now. The project also introduces Baltimore City high school students to mathematics and molecular biophysics through unique visualization activities.The essence of combining domains is geometric. The team can use articulated multi-rigid-body models from the field of robotics to combine rigid portions of structures, from domains with similar sequences. The relative rigid-body motions between the domains become the unknown degrees of freedom in these articulated models. Crystal packing constraints will rule out the majority of possible configurations for these domains, and reduce the otherwise high-dimensional nature of the search space. The project will develop new algebro-geometric and computational methods for rapidly discarding the large collision regions in configuration space, so that searches will focus on the remaining small-volume feasible regions in this high-dimensional search space. Computer code will be prepared integrating the resulting methods into existing molecular crystallography software packages.

该 INSPIRE 项目由 CISE/CCF 算法基金会、MPS/DMS 分析和 NSF 综合活动办公室联合资助。蛋白质分子 3 维结构的知识支持对蛋白质如何在细胞内发挥其功能的科学理解。蛋白质数据库中超过 100,000 个蛋白质的结构已通过大分子 X 射线晶体学确定：测量由一个或多个蛋白质分子的许多对称排列副本组成的晶体的 X 射线束的衍射，给出必须填写的部分信息（傅里叶变换的振幅）（解决“相位问题”，通常通过分子替换——从相关的相位中获取相位）。分子）来完成 3D 结构。分子替换对于简单的单结构域蛋白质非常有效，但对于多结构域蛋白质和大型复合物则失效；人们需要探索域及其衍射图案的可能组合作为替代候选者。这个跨学科项目汇集了机器人技术和纯数学领域的专家，以解决大分子 X 射线晶体学的“相位问题”。该项目开发的数学和计算框架将使更多的蛋白质结构能够以比现在更省力的方式得到解决。该项目还通过独特的可视化活动向巴尔的摩市的高中生介绍数学和分子生物物理学。组合领域的本质是几何学。该团队可以使用机器人领域的铰接式多刚体模型来组合来自具有相似序列的领域的结构的刚性部分。域之间的相对刚体运动成为这些铰接模型中的未知自由度。晶体堆积约束将排除这些域的大多数可能配置，并减少搜索空间的高维性质。该项目将开发新的代数几何和计算方法，用于快速丢弃配置空间中的大碰撞区域，以便搜索将集中在这个高维搜索空间中剩余的小体积可行区域。将准备计算机代码，将所得方法集成到现有的分子晶体学软件包中。