Rapid Computational Analysis of Biomolecular Properties

项目摘要 本提案中所述研究的目的是开发用于分析生物大分子三维结构的快速计算工具。 目标是将联合收割机图形技术与数值和理论方法结合起来，图形技术旨在突出大分子的功能重要特征，数值和理论方法允许用户提取有意义的数字 一些重要的物理性质 三维结构这种类型的能力已被纳入 GRASP（Graphical Representation） 和结构特性分析）计算机程序，该程序是在本资助期内开发的。在过去的三年中，GRASP演变成结构生物学中最广泛使用的分析工具之一。目前提案的一个目标是继续发展大型类人猿生存项目，使其更广泛地得到利用，并通过 加入新的功能， 新的定量分析工具。 GRASP的主要应用是计算和表示蛋白质和核酸在分子表面上的静电势。 计算了电势 从 有限差分 解决方案 到 Poisson-Boltzmann（PB）方程基本上是从本实验室开发的德尔菲程序中使用的相同算法获得的。蛋白质新结构的报告通常包括一个或多个代表PB方程解的GRASP图片。 然而，Silicon Graphics工作站需要描绘这些图像，这在一定程度上限制了它们的使用。 为了使GRASP图像更广泛地使用，我们计划将GRASP中的图形例程转换为VRML中的输出图形描述， 万维网（WWW）。 我们还计划采用接口工具，这将便利与其他方案的交流，简化使用现有功能的学习曲线，并使在大型类人猿生存项目中纳入新的定量分析工具成为可能。 本提案的第二个目标是为整个蛋白质数据库（PDB）创建GRASP图像数据库。 GRASP分子表面的静电势和曲率图像将为每种蛋白质创建PDB并将其存储在数据库中。 2D和3D GRASP图像将可在万维网上查看。预计这些图像的广泛可用性将导致新的结构-功能关系的发展，并最终导致新的基于表面的数据库的创建，这将使得有可能推导出给定三维结构的功能和功能活性区域。该提案的最终目标是将定量分析工具纳入大型类人猿生存项目。 特别地，用户将能够实时地获得屏幕上以图形方式描绘的任何结构的pKais溶剂化、构象和结合自由能。 拟议的研究对知识进步的重要性体现在大型类人猿生存项目的成功上， 已经证明了交互式定量分析工具对分析大分子结构和功能关系的影响。 表面特性数据库， 新的GRASP功能的增加应该对利用蛋白质和核酸的三维结构中包含的大量信息的能力具有可比的影响。

Project Summary The purpose of the research described in this proposal is the development of rapid computational tools for the analysis of the three dimensional structure of biological macromolecules. The goal is to combine graphical techniques designed to highlight functionally important features of macromolecules with numerical and theoretical methods that allow a user to extract meaningful numbers about important physical properties from a three dimensional structure. Capabilities of this type of have been incorporated into the GRASP (Graphical Representation and Analysis of Structural Properties) computer program which was developed in the current funding period. In the past three years GRASP evolved into one of the most widely used analysis tools in Structural Biology. A goal of the current proposal is to continue the development of GRASP by making it more widely accessible and through the incorporation of new functionalities and new quantitative analysis tools. The major application of GRASP has been the calculation and representation of the electrostatic potentials of proteins and nucleic acids on the molecular surface. The potentials are calculated from finite-difference solutions to the Poisson-Boltzmann (PB) equation obtained from essentially the same algorithm used in the DelPhi program which was also developed in this lab. It has become commonplace for the report of a new structure of a protein to include one or more GRASP pictures representing solutions to the PB equation. However Silicon Graphics workstations are required to depict these images, a factor which has to some extent limited their use. In order to make GRASP images more widely available, we plan to convert the graphical routines within GRASP to output graphical descriptions in VRML, the 3D scene description language proposed for the World Wide Web (WWW). We also plan to introduce interfacing tools which will facilitate communication with other programs, will simplify the learning curve for the use of current functionalities and will make it possible to integrate new quantitative analysis tools within GRASP. A second goal of the current proposal is the creation of a database of GRASP images for the entire Protein Data Base (PDB). GRASP molecular surface images of electrostatic potential and curvature will be created for each protein in the PDB will be stored in a database. 2D and 3D GRASP images will be made available for viewing over the WWW. It is anticipated that the wide availability of these images will lead to the development of a new structure-function relationships and, ultimately, to the creation of new surface-based data bases which will make it possible to deduce function and functionally active regions given a three dimensional structure. The final goal of the proposal is the integration of quantitative analysis tools within GRASP. In particular, a user will be able, in real-time, to obtain pKais solvation, conformational and binding free energies for any structure depicted graphically on the screen. The significance of the proposed research to the advancement of knowledge is manifest in the success of GRASP which has demonstrated the impact of interactive quantitative analysis tools on the analysis of macromolecular structure and function relationships. The database of surface properties and the addition of new GRASP functionalities should have comparable impact on the ability to exploit the vast amount of information embodied in the three dimensional structure of proteins and nucleic acids.