Rapid Computational Analysis of Biomolecular Properties

项目概述本提案中描述的研究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。其目标是将旨在突出大分子重要功能特征的图形技术与数值和理论方法相结合，使用户能够从三维结构中提取有关重要物理性质的有意义的数字。这种类型的能力已被纳入在本供资期间开发的GRASP(结构特性的图形表示和分析)计算机程序。在过去的三年中，GRAP发展成为结构生物学中使用最广泛的分析工具之一。目前提案的一个目标是继续开发GRAPH，使其更广泛地使用，并纳入新的功能和新的量化分析工具。GRAP的主要应用是计算和表示蛋白质和核酸在分子表面的静电势。势是从泊松-玻尔兹曼(PB)方程的有限差分解中计算出来的，该方程的算法基本上与本实验室开发的Delphi程序中使用的算法相同。对于蛋白质新结构的报道，包括一张或多张代表PB方程解的GRAPH图已经变得司空见惯。然而，需要Silicon Graphics工作站来描绘这些图像，这一因素在一定程度上限制了它们的使用。为了使GRAP图像更广泛地使用，我们计划将GRAP中的图形例程转换为VRML格式的图形描述，VRML是为万维网(WWW)提出的3D场景描述语言。我们还计划引入接口工具，这些工具将促进与其他程序的交流，将简化使用现有功能的学习曲线，并将使在GRAP中集成新的量化分析工具成为可能。当前提议的第二个目标是为整个蛋白质数据库(PDB)创建GRAPH图像数据库。GRAPH分子表面的静电势和曲率图像将被创建，将每个蛋白质的PDB存储在一个数据库中。2D和3D GRAPH图像将可通过WWW查看。预计这些图像的广泛使用将导致开发新的结构-功能关系，并最终创建新的基于表面的数据库，从而能够在给定三维结构的情况下推断功能和功能活跃区域。该提案的最终目标是在GRAPH中整合量化分析工具。具体地说，用户将能够实时地获得屏幕上图形描绘的任何结构的pKais溶剂化、构象和结合自由能。所提出的研究对知识进步的意义体现在GRAPH的成功中，这表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。表面属性数据库和新的GRAP功能的增加应该对利用蛋白质和核酸三维结构中所包含的大量信息的能力产生类似的影响。

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.