Informatics/modeling/extend/NMR structure determination

产品说明： 这项研究的长期目标是通过在信息学中开发新的基于物理学的模型来显著加快对蛋白质的理解。蛋白质参与了大量的生物功能，它们与许多疾病和病症的关联使得及时了解它们的结构成为与人类健康具有重大相关性的主题。作为理解蛋白质的一个步骤，开发一个广泛的蛋白质结构清单及其快速分析被指定为结构生物学的一个关键目标。实验方法将继续发挥关键作用，因为大量的新蛋白质折叠仍然未被探索。NMR光谱是分析蛋白质结构的关键实验工具，并且存在简化和扩展其范围的强烈需求。这项工作的主要研究重点是调查和工具的进步，这将导致显着加速理解蛋白质结构，通过建立一个概率框架，集成信息学和物理模型。该策略是联合收割机的使用信息学工具和所需的物理建模，以快速评估，合并多个数据源，并促进有效的建设和分析蛋白质库存。所提出的方法已经导致创新的工具，已经证明了量化的进展，在实践中的NMR结构测定。申请人在此资助期间有三个研究目标：1）研究将PI开发的现有工具结合成一个完整范例的方法，目的是解决小到中等大小蛋白质的快速和稳健的结构测定，（二）研究方法的蒸馏和扩展，使其成为一套核心工具，可以为快速确定蛋白质折叠和结构的新工具奠定基础。更大的蛋白质，以及3）采取探索性的步骤来理解“每个新工具对我们理解蛋白质空间有多大贡献”的问题。“这些方法背后的基本思想是设计一系列物理模型，并使用信息学工具找到最‘成功’的模型。这些工具将通过加速和简化结构确定中实验数据的使用，促进及时产生有关蛋白质功能的信息。对蛋白质理解的加速进展将对促进人类健康的保障产生直接和重大的影响。

DESCRIPTION: The long-term goal of this research is to provide significant speed-ups in understanding proteins through development of novel physics-based models in informatics. Proteins are involved in a large array of biological functions and their association with numerous diseases and disorders makes the timely understanding of their structure a subject with significant relevance to human health. As a step toward understanding proteins, the development of a broad inventory of protein structures and their rapid analysis is designated as a critical goal of structural biology. Experimental methods will continue to play a critical role, as a large number of novel protein folds remain unexplored. NMR spectroscopy is a key experimental tool in analyzing protein structures and a strong need for streamlining and extending its reach exists. The primary research focus of this work is the investigation and advancement of tools that will lead to significant speedups in understanding protein structures by building a probabilistic framework that integrates informatics and physical models. The strategy is to combine the use of informatics tools and physical modeling that is needed in order to rapidly evaluate, merge multiple data sources, and facilitate efficient building and analysis of protein inventories. The proposed approach has already lead to innovative tools that have demonstrated quantifiable advances in the practice of NMR structure determination. The applicant has three research goals during this grant period: 1) investigate approaches to combining present tools developed by the PI into a complete paradigm with the aim of addressing fast and robust structure determination of small to moderate size proteins, 2) investigate distillation and extension of methods into a set of core tools that could form the basis for novel tools for rapid determination of protein folds and structure of larger proteins, and 3) take exploratory steps toward understanding the question of "how much each new tool contributes to our understanding of protein space." The basic idea behind these methods is to devise a family of physical models and use informatics tools to find the most 'successful' model. These tools will facilitate production of timely information regarding proteins' functions by speeding up and streamlining the use of experimental data in structure determination. The accelerated progress toward understanding proteins will have a direct and significant impact on advancing the safeguards of human health.