Docking Protein Densities

The structure of protein assemblies is largely determined by non-covalent interactions betweenproteins. The importance of shape complementarity of interacting molecular surfaces is generallyrecognized, but it is not easily studied, due to difficulties in quantifying shape. This proposal will developmethods for (1) characterizing the shape of protein surfaces, and (2) predicting complexes betweenproteins of known three-dimensional structure. The methods will be designed to work, even if thesurface amino acid side chains have indeterminate orientation, as is often the case in proteincrystallographic studies. Conformational flexibility will be modeled as partial occupancy (density) on athree-dimensional grid. The side chains' averaged density will be used for shape measurement. Areliable protein-docking computer program will be a quicker and less expensive means to study a proteinassociation than an x-ray crystallographic experimental study of the complex. Applications include: (1)predicting how a monoclonal antibody binds to its protein antigen, (2) the assembly of viral coat proteinmonomers into capsides, and (3) the genetic disease sickle cell anemia, where hemoglobin monomersassociate in an incorrect way. The software developed will be licensed to academic, governmental andindustry scientists researching the molecular basis of disease.