The long-range goals of the proposed research are; a) developing computational tools for the calculation of the physical properties of proteins based on three dimensional structure, b) protein-structure prediction, c) understanding the structural and energetic origins of specificity in protein-protein interactions. The specific goals of the current proposal include the development of new methods for homology modeling and studies on specificity determinants in the cadherins, a family of cell-cell adhesion proteins. The health relatedness of the proposed research involves the development of tools for a variety of biological applications and the discovery of new insights about fundamental biological processes such as those involved in tissue formation. The proposed research on homology modeling includes: 1) the development, testing and application of methods to evaluate the conformational energies of proteins and to refine three dimensional structures; 2) the development, testing and application of methods for structure-based sequence alignment; 3) the development of a new approach for generating "suboptimal" alignments and evaluating models that are generated from these alignments based on conformational energies and other scoring functions. The work on cadherins involves applications of many of the methods being developed. Cadherins are a family of proteins present on the surfaces of the cells that mediate selective intercellular adhesion. The goal of the proposed research is to understand how cadherin domains, many of which have high degrees of sequence and structural similarity, can bind to one another in a specific manner. The work involves a collaborative experimental component. The computational work involves studying specificity determinants in cadherin domains whose structure are known, the construction of homology models for other family members, and the use of the various structures to identify key residues that play a role in specificity. [unreadable] [unreadable] [unreadable] [unreadable]