CAREER: A Database for Modeling Protein Spatial Geometry -Discovering Protein Functions

细菌、植物、真菌、蠕虫、果蝇和人类中的许多基因都没有序列匹配，它们的三维结构尚未解决，它们的功能也不清楚。关键残基的三维空间表面基序可以提供连接基因序列、蛋白质结构和蛋白质功能的关键纽带。具有复杂几何结构的表面基序很难计算，关键残基往往来自初级序列的较远部分。拟议的项目旨在开发利用计算几何学发现相似蛋白质表面模式的工具，以及用于生物查询和理解的相似蛋白质表面数据库的服务器数据库。搜索工具将使用综合信息学方法开发，以发现蛋白质表面的统计上显著的相似关系，结合序列、物理化学和形状信息。空间表面基序数据库将提供丰富的功能注释的有组织的信息，通过提供定量的、有组织的和可理解的蛋白质表面基序信息，所提出的工具和数据库将有助于揭示表面基序中关键残基的新模式，对理解蛋白质功能具有重要意义。它将有助于从基因组测序中了解新测序基因的细胞作用，以及从结构基因组学中了解新解决的结构。这也将有助于建立以前未知的蛋白质空间表面的功能和进化关系，并在蛋白质结构域和折叠出现之前揭示功能受限结构元素的深层进化起源。从蛋白质表面基序获得的知识和洞察力也将有助于为新的生物功能和新的工业应用设计和设计新的蛋白质。这项建议的教育部分将集中在(1)课程和课程开发，(2)学生指导，和(3)推广。除了为新批准的生物信息学硕士/博士课程开发课程外，还将开发一门名为“生物信息学的几何计算”的新课程，该课程将通过课堂教学和基于研究活动设计的课堂项目与研究紧密联系起来。研究生和本科生以及博士后研究人员的参与提供了指导机会，目的是将知识、计算技能以及批判性和创造性思维的能力传授给学生。它还将允许学生在国内和国际会议上展示他们的研究成果。芝加哥高中和专科学校的外展活动将侧重于生物信息学研究的高中夏令营活动、当地访问、在PI的实验室接待实习生、学校教师准备和发展职业以及生物信息学教育材料(光盘和网站)，以吸引传统上没有这一领域代表的学生。

Many genes in bacteria, plants, fungi, worm, fruit fly, and human have no sequence matches, their three-dimensional structures are unsolved, and their functional roles are unknown. Three-dimensional spatial surface motifs of key residues can provide critical links connecting gene sequence, protein structure, and protein functions. Surface motifs with complicated geometry are difficult to compute, and the key residues are often from distant parts of the primary sequences. The proposed project aims to develop tools using computational geometry for discovery of similar protein surface patterns, as well as server databases of libraries of similar protein surfaces for biological querying and understanding. The search tools will be developed using a comprehensive informatics approach for discovery of statistically significant similarity relationship of protein surfaces, combining sequence, physicochemical, and shape information. The database of libraries of spatial surface motifs will provide organized information enriched with functional annotation.By providing quantitative, organized, and understandable information of protein surface motifs, the tools and database proposed will help to uncover new patterns of key residues in surface motifs important for understanding protein functions. It will facilitate the understanding of the cellular roles of newly sequenced genes from genomic sequencing and newly solved structures from structural genomics. It will also help to establish previously unrecognized functional and evolutionary relationship of protein spatial surfaces, and uncover deep evolutionary origins of functionally constrained structural elements before the emergence of protein domains and folds. Knowledge and insight gained from protein surface motifs will also help to design and engineer novel proteins for new biological functions and for novel industrial applications.The educational component of this proposal will be centered on (1) course and curriculum development, (2) student mentoring, and (3) outreach. In addition to curriculum development for the newly approved MS/PHD programs in bioinformatics, a new course named "Geometric Computing for Bioinformatics" will be developed, which will be tightly linked to the research through classroom teaching and class projects designed based on the research activities. The involvement of graduate and undergraduate students, as well as postdoctoral researchers provide mentoring opportunities, with the goal to pass the knowledge, the computational skill, and the ability of critical and creative thinking to the students. It will also allow the students to present their research in national and international conferences. The outreach activities to Chicago high school and junior colleges will be focused on high school summer camp activities of bioinformatics research, local visits, hosting interns in the PI's lab, school teacher preparation, and developing career as well as educational material on bioinformatics (CD-ROM and website) to attract students not traditionally represented in this field.