Rapid Computational Analysis of Biomolecular Properties

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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.