IMP: Software for Hybrid Determination of Macromolecular Assembly Structures

项目摘要 其主要目标是开发和应用计算方法来建立蛋白质和蛋白质的结构模型 他们的集会。这些模型可以深入了解组装如何工作，它们是如何发展的，它们如何 以及如何设计类似的功能。一种成功的方法，一体化结构- 真确定，将这样的模型的建立作为计算优化问题来处理，其中 关于组件的知识被编码到用于评估候选模型的评分函数中。我们 建议扩展和增强集成建模平台(IMP；http://integrativemodeling.org) 为开发和分发集成结构建模协议提供编程支持。小鬼 允许使用来自多种类型数据的空间限制以多个分辨率表示分子，以及 通过各种采样算法寻找解决方案。到目前为止，它主要应用于电子微电子领域。 显微镜、质谱学、小角X射线散射、Förster共振能量转移、交联、 以及各种蛋白质组学数据。IMP很容易扩展以添加对新数据源和算法的支持，并且 是在开源许可下分发的。在这里，我们建议扩展IMP以解决更大范围的生物- 并使其更普遍地对科学界有用。具体来说，在目标1中，我们将 设计和测试适合的分子表示、评分函数和构象采样方案 对于部分基于氢-氚交换数据的建模，该数据由核磁共振率确定- 声谱或质谱学；评分函数将依赖于贝叶斯方法来提取 从数据中获取最大的结构和动态信息。在目标2中，我们将重点放在优化系统 用于综合结构确定的表示法。特别是，我们将探索如何找到最优的 在给定输入信息的情况下，通过对依赖于 几种方法，包括贝叶斯推理方法。在目标3中，我们将最大限度地发挥IMP对 社区，通过提供一个经过良好测试和维护的软件包，该软件包随邮件一起记录 清单、范例、在当地和外部研讨会上的演示，以及在加州大学旧金山分校和由 寻求与其他软件包和社区资源更紧密地集成，包括数据库 作为蛋白质数据库，结构查看器，如Chimera，和Web门户，如蛋白质模型POR- 塔尔。拟议的目标是由新成立的世界蛋白质数据库在REP- 怨恨、确认、存档和传播社区产生的一体化结构模型。

Project Summary The broad goal is to develop and apply computational methods for building structural models of proteins and their assemblies. These models can give insights into how the assemblies work, how they evolved, how they can be controlled, and how similar functionality can be designed. One successful approach, integrative struc- ture determination, casts the building of such models as a computational optimization problem where knowledge about the assembly is encoded into the scoring function used to evaluate candidate models. We propose to extend and enhance the Integrative Modeling Platform (IMP; http://integrativemodeling.org) that provides programmatic support for developing and distributing integrative structure modeling protocols. IMP allows representing molecules at multiple resolutions, using spatial restraints from many types of data, and searching for solutions by a variety of sampling algorithms. So far, it has been applied mostly to electron mi- croscopy, mass spectrometry, small angle X-ray scattering, Förster resonance energy transfer, crosslinking, and various proteomics data. IMP is easily extensible to add support for new data sources and algorithms, and is distributed under an open source license. Here, we propose to extend IMP to address a greater range of bio- logical problems and make it more generally useful to the scientific community. Specifically, in Aim 1, we will design and test a molecular representation, a scoring function, and a conformational sampling scheme suitable for modeling based in part on hydrogen deuterium exchange data, determined either by nuclear magnetic res- onance spectroscopy or mass spectrometry; the scoring function will rely on a Bayesian approach to extract the maximum structural and dynamic information from the data. In Aim 2, we will focus on optimizing system representations for integrative structure determination. In particular, we will explore how to find an optimal coarse-grained representation, given the input information, by sampling alternative representations relying on several methods, including a Bayesian inference approach. In Aim 3, we will maximize the impact of IMP on the community, by delivering a well-tested and maintained software package that is documented with mailing lists, examples, demonstrations at local and external workshops, and hosting of select users at UCSF, and by pursuing closer integration with other software packages and community resources, including databases such as the Protein Data Bank, structure viewers such as Chimera, and web portals such as the Protein Model Por- tal. The proposed aims are informed by and will shape the nascent Worldwide Protein Data Bank effort on rep- resenting, validating, archiving, and disseminating integrative structure models produced by the community.