This proposal describes asymmetric syntheses of 2.3-methanoamino acids (1-aminocyclopropanecarboxylic acids) and investigations of the effects of these on the secondary structures and functions of peptides that incorporate them. Very few uses of 2.3-methanoamino acids have been reported, despite their numerous potential applications in biological and medicinal chemistry. This is presumably due to the difficulties encountered in preparing stereochemically pure samples. Described here are asymmetric syntheses of several side-chain functionalized 2.3- methanoamino acids via routes which should hive gram amounts in optically pure form. Specifically, analogs of Arg, Glu, Phe, Tyr, Leu, Ile, Val, and His will be prepared. The availability of substantial quantities of stereoisomerically pure 2.3-methanoamino acids will facilitate, for the first time, biophysical studies wherein standard systems incorporating these "methanologs" will be analyzed by CD to access the stabilizing or destabilizing effects of these amino acids in helical peptides. Two applications of 2.3-methanoamino acids are proposed to illustrate the potential of 2.3-methanoamino acids. The first involves substitution of 8Phe, 12His, and 2Glu of the RNase A C-peptide. The mutagenesis will perturb two interactions widely regarded as critical for stabilizing the a-helical structure of the C-peptide: perpendicular p-stacking between 8Phe-12HIs+, and ionic interactions between 2Glu and 10Arg. Moreover, 12His is a key residue in the active site of RNase A and, presumably, the RNase C-peptide "two component enzyme". the enzymatic activity of the mutated two component system will be studies to facilitate correlations between this, the a-helicity of the C-peptide, and side chain orientations (particularly in the active site of the two component enzyme system). Interpretations of these results will be aided by graphical representations obtained via molecular mechanics and NMR studies. The work outlined above will reveal the effects of single substitutions of methanologs for natural amino acids, and for RNase A it may be reasonable to study the effects of two distant substitutions. Such changes are unlikely to lock peptides into one relatively rigid conformation, however. The last application proposed utilizes two methanologs in sequence, giving highly constrained systems. The effects of placing two methanologs in series are most probably severe and are almost completely unknown. Thus, potential inhibitors of HIV proteases containing 2.3-methanoamino acids will be prepared and examined for inhibition of HIV proteases, and for their effects on HIV-1 infected cells. They will have two methanologs to project the side chains in various orientations to fill hydrophobic pockets in the enzyme. They may be competitive inhibitors, but they also have the potential to bind to the HIV proteases irreversibly. Molecular dynamics and 2D NMR studies will be used to rationalize which compounds of this type fit most comfortably into the active site of HIV-1 protease and will provide an insight into the effects of placing methanologs in sequence.