Integrative Structure Modeling of the Core SPB

核心SPB的综合结构建模

• 批准号: 8668225
• 负责人: ANDREJ SALI
• 金额: $ 22.65万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8668225
• 关键词: 26S proteasome; Accounting; Algorithms; Bayesian Method; Benchmarking; Centrosome; Cereals; Complex; Computer software; Coupled; Crystallography; Data; Data Collection; Data Sources; Electron Microscopy; Energy Transfer; Family; Freedom; Hand; Homology Modeling; Individual; Measurement; Methods; Modeling; Multiprotein Complexes; Nature; Noise; Nuclear Pore Complex; Positioning Attribute; Principal Investigator; Probability; Process; Proteins; Protocols documentation; Resolution; Roentgen Rays; Sampling; Solutions; Spectrum Analysis; Staging; Structural Models; Structure; System; Uncertainty; Yeast Model System; Yeasts; base; crosslink; density; improved; macromolecular assembly; multicatalytic endopeptidase complex; open source; restraint; satisfaction; spindle pole body

Structural modeling of a macromolecular assembly is best cast as a computational optimization problem where information about the assembly is encoded into the scoring function used to evaluate candidate models. To this end, we are developing IMP, the Integrative Modeling Platform (9) (http://inteqrativemodelinq.orq/), an open source software package to construct spatial models of large macromolecular protein complexes by satisfaction of spatial restraints from a variety of experimental data. IMP was demonstrated by application to several complexes, including the Nuclear Pore Complex (4) and the 26S proteasome (11). We will use IMP inan iterative experimental and computational process to construct a pseudo-atomic resolution model of the Yeast Spindle Pole Body (SPB). The spatial restraints for model construction will be derived from the currently available data as well as new data generated in the proposed POl center. We will first improve, develop, and benchmark computational protocols for using crystallography, electron microscopy (EM), small angle X-ray scattering (SAXS), Forster resonance energy transfer (FRET) spectroscopy, and cross-linking data for integrative structure modeling ofthe SPB. Incompleteness, noise, and ambiguity in experimental data will be treated using an inference-based scoring function that will extract the maximum possible information from the data, following a Bayesian approach with minimal assumptions and approximations (13). Sampling all model structures consistent with the data is generally,a challenging problem, in part due to the rugged nature ofthe scoring function landscape and its many local minima. To this end, we will develop a sampling method that efficiently divides the complete set of degrees of freedom into potentially overiapping subsets, finds candidate' solutions for the subsets independently by traditional optimizers or enumeration, and then combines compatible solutions to obtain guaranteed best-scoring solutions for the whole system (15). Finally, we will apply these scoring and sampling methods to determine the pseudo-atomic structure of the SPB. PHS 398/

大分子组装的结构建模最好是作为一个计算优化问题， 关于组件的信息被编码到用于评估候选模型的评分函数中。到 为此，我们正在开发IMP，集成建模平台（9）（http：//inteqrativemodelinq.orq/）， 开源软件包，通过满意度构建大分子蛋白质复合物的空间模型 空间限制的各种实验数据。IMP通过应用于几个 复合物，包括核孔复合物（4）和26 S蛋白酶体（11）。我们将使用IMP 迭代实验和计算过程，以构建酵母的伪原子分辨率模型 主轴极体（SPB）。模型构建的空间限制将从当前可用的 数据以及在提议的POI中心中生成的新数据。我们将首先改进、发展， 使用晶体学、电子显微镜（EM）、小角度X射线 散射（SAXS），福斯特共振能量转移（FRET）光谱，和交联数据的整合 SPB结构建模将处理实验数据中的不完整性、噪音和模糊性 使用将从数据中提取最大可能信息的基于推理的评分函数， 遵循具有最小假设和近似值的贝叶斯方法（13）。对所有模型结构进行采样 与数据的一致性通常是一个具有挑战性的问题，部分原因是评分的粗糙性 函数景观及其许多局部极小值。为此，我们将开发一种抽样方法， 将完整的自由度集划分为可能重叠的子集， 通过传统的优化器或枚举法对子集独立地进行优化，然后组合相容的 解决方案以获得整个系统的保证最佳得分解决方案（15）。最后，我们将应用这些 评分和取样方法来确定SPB的伪原子结构。 小灵通398/