Rapid Computational Analysis of Biomolecular Properties

项目总结拟议研究的主要目标是开发用于分析涉及生物大分子的分子间相互作用的计算工具。由于这种相互作用主要局限于分子表面，将特别强调用于绘制、分析和比较分子表面物理和化学性质的数据库、软件和算法。拟议的研究建立在前几个资助期开发的GRASH(结构属性的图形表示和分析)方案中体现的概念之上。GRAPH的广泛使用导致需要继续开发和整合目前可获得的越来越多的序列、结构和功能数据，特别是来自基因组测序项目的数据。与此同时，越来越多的蛋白质三维结构已被确定，以及结构预测的进展，这为开发从结构中提取功能信息的新方法提供了需求和机会。拟议研究的具体目标包括：1)开发一种新版本的GRASP，具有更强的通用性和便携性，并增强了计算静电势、结合五能和pKas等分子性质的能力。该程序将基于一个新的、多平台的、面向对象的软件库，具有方便的程序员和用户界面，以实现最大的灵活性、可扩充性和可用性。2)利用该程序构建和查询一个全新类型的数据库，该数据库将包含蛋白质表面和蛋白质形成的界面的几何、物理、化学和生物描述，该研究将对理解涉及生物大分子的分子识别原理产生重大影响。将开发的工具将由结构生物学家、分子生物学家和生物化学家使用，他们对将结构信息和生物物理方法整合到他们的研究计划中感兴趣。此外，这项提议代表着将基因组信息、结构信息、物理化学原理、数学算法和软件开发整合到一个统一的研究计划中的努力。涉及的跨学科研究和培训应增加结构基因组学这一新兴领域的科学和人力资源基础设施。

PROJECT SUMMARYThe major objective of the proposed research is the development of computational tools for the analysis of intermolecular interactions involving biological macromolecules. Since such interactions are primarily localized at the molecular surface, particular emphasis will be placed on databases, software, and algorithms for the mapping, analysis and comparison of physical and chemical properties on the molecular surface. The proposed research builds on concepts embodied in the GRASP (Graphical Representation and Analysis of Structural Properties) program which was developed in previous funding periods. The widespread use of GRASP has led to the need for its continued development and integration with the growing body of sequence, structural and functional data currently becoming available, particularly from genome sequencing projects. In parallel, the increasing number of three dimensional protein structures that have been determined, as well as progress in structure prediction has produced both a need and an opportunity for the development of new approaches aimed at extracting functional information from structure.The specific goals of the proposed research include: 1) The development of a new version of GRASP with greater generality and portability and enhanced capabilities to calculate molecular properties such as electrostatic potentials, binding five energies and pKas. The program will be based on a new, multi-platform, object-oriented software library with convenient programmer and user interfaces so as to allow maximum flexibility, extendibility and usability. 2) The use of this program to construct and interrogate a fundamentally new type of database that will contain geometric, physical, chemical and biological descriptions of protein surfaces and interfaces formed by proteins.The proposed research will have significant impact on the understanding of the principles of molecular recognition involving biological macromolecules. The tools to be developed will be used by structural biologists, molecular biologists and biochemists interested in integrating structural information and biophysical methods into their research programs. In addition, this proposal represents an effort to integrate genomic information, structural information, physical chemical principles, mathematical algorithms and software development into a unified research program. The interdisciplinary research and training involved should add to both the scientific and human resource infrastructure of the emerging area of Structural Genomics.