IMP: Software for Hybrid Determination of Macromolecular Assembly Structures

项目摘要 广泛的目标是开发和应用计算方法来建立蛋白质的结构模型， 他们的集会。这些模型可以让我们深入了解这些组件是如何工作的，它们是如何进化的，它们是如何被 可以控制，以及如何设计类似的功能。一个成功的方法，综合结构， 真实的确定，铸造作为计算优化问题，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。Imp 允许以多种分辨率表示分子，使用来自多种类型数据的空间约束， 通过各种采样算法搜索解决方案。到目前为止，它主要应用于电子显微镜， 色谱法，质谱法，小角X射线散射，Förster共振能量转移，交联， 和各种蛋白质组学数据。IMP易于扩展以添加对新数据源和算法的支持， 是在开放源代码许可下发布的。在这里，我们建议扩展IMP，以解决更大范围的生物- 逻辑问题，并使其更普遍地对科学界有用。具体而言，在目标1中，我们将 设计并测试分子表示、评分函数和构象采样方案， 用于部分基于氢氘交换数据的建模，所述氢氘交换数据通过核磁共振确定， 单次光谱或质谱;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，我们将专注于优化系统 用于综合结构确定的表示。特别是，我们将探讨如何找到一个最佳的 粗粒度表示，给定输入信息，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国际货币基金组织在以下方面的影响： 通过交付经过良好测试和维护的软件包， 列表，示例，在本地和外部研讨会上的演示，以及在UCSF选择用户的托管，以及 寻求与其他软件包和社区资源，包括数据库， 如蛋白质数据库，结构查看器，如嵌合体，和门户网站，如蛋白质模型Por- tal.拟议的目标是由新生的世界蛋白质数据库的努力，并将塑造复制， 对社区产生的综合结构模型进行重新报告、验证、存档和传播。

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.