Rapid Computational Analysis of Biomolecular Properties

PROJECT SUMMARY

The 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.