SBIR-STTR Award

The structure of protein assemblies is largely determined by non-covalent interactions between proteins. The importance of shape complementarity of interacting molecular surfaces is generally recognized, but it is not easily studied, due to difficulties in quantifying shape. This proposal will develop methods for (1) characterizinzthe shape of protein surfaces, and (2) predicting complexes between proteins of known three-dimensional structure. The methods will be designed to work, even if the surface amino acid side chains have indeterminate orientation, as is often the case in protein crystallographic studies. Conformational flexibility will be modeled as partial occupancy (density) on a three-dimensional grid. The side chains' averaged density will be used for shape measurement. A reliable protein-docking computer program will be a quicker and less expensive means to study a protein association than an x-ray crystallographic experimental study of the complex. Applications include: (1) predicting how a monoclonal antibody binds to lts protein antigen, (2) the assembly of viral coat protein monomers into capsides, and (3) the genetic disease sickle cell anemia, where hemoglobin monomers associate in an incorrect way. The software developed will be licensed to academic, governmental and industry scientists researching the molecular basis of disease.Awardee's statement of the potential commercial applications of the research:The computer software developed will be licensed to pharmaceutical and biotechnology companies for use in designing proteins to be used as pharmaceuticals.National Institute of General Medical Sciences (NIGMS)

The purpose of the proposed research is to develop computer methods to predict the three-dimensional structures of protein complexes, given the three-dimensional structures of the individual protein components. A special goal of this work is to take into account the fact that there is some conformational variation at protein surfaces, due to the motions of the atoms at the surface. Each protein is represented by a cubical lattice of occupancies or densities, which are numbers between 0.0 and 1.0 describing how much of the time that cube is occupied by the protein's atoms. For cubes in the interior of the protein, the densities will be 1.0. The shapes of these soft or fuzzy surfaces will be analyzed, and complementary shapes will be docked together in the computer. Protein-protein docking predictions should be useful in (1) the assembly of viral coat protein monomers into capsids, (2) the genetic disease sickle cell anemia, where there is unwanted polymerization of hemoglobin subunits, (3) understanding antibody-antigen recognition, (4) understanding the mechanisms of protein toxins, such as diphtheria and cholera toxins, and (5) designing protein drugs. PROPOSED COMMERCIAL APPLICATION: The computer software developed during this project will be licensed to pharmaceutical and biotechnology companies for use in designing proteins to be used as pharmaceuticals. It will also be licensed, for a more modest fee, to universities and research institutes.

Thesaurus Terms:
computer program /software, computer system design /evaluation, protein structure