The amino acid sequence of a protein uniquely determines its tertiary structure. Deciphering this relationship, the protein folding problem has become increasingly important to molecular biologists. With the dramatic progress of the genome initiatives within the public and private sector and the push for a structural genomics initiative in the post-genomic era, the need for computational strategies to relate protein sequence to protein structure become even more profound. This proposal describes new directions in our effort to improve the accuracy of protein secondary structure and to use these results and others to improve the results of threading algorithms that map new sequences onto existing structures. We continue to be impressed by the information inherent in a family of protein sequences, especially when viewed from an evolutionary perspective. A study of the ligand binding domain and the corresponding ligands of intranuclear hormone receptors is planned. This effort will link computation, molecular biology and synthetic chemistry efforts to better understand this pharmacologically exciting group of molecules. In addition, an evolutionary trace strategy is described that could lead to the identification of pairs of covarying residues within a family of aligned sequences. Success in this arena would have important implications for threading algorithms. Finally, work on the design of a novel class of abiologic sturctured heteropolymers is described that builds on our recent results with N-alkylated glycines.