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Aromatic amines are indirectly acting carcinogens requiring multiple metabolic transformation to hydroxylamines and their ultimate active form. Current evidence implicates arylnitrenium ions as the ultimate carcinogen of this class of compounds. Using semiempirical molecular orbital methods, the electronic parameters related to metabolic activation and the stability and electro-philicity of these ultimate carcinogens were calculated for a series of aromatic amines. In addition, both semiempirical quantum mechanical perturbation and empirical potential methods have been used to characterize incipient covalent complexes of arylnitrenium ions with guanine and adenine. Such complexes could be intermediates in adduct formation at different base sites. The results of these studies are used to correlate to carcinogenic or mutagenic activity and to obtain insight into the specificity of adduct formation with DNA.

Conformational similarities of Met-enkephalin and its D-Ala2 analogue to rigid opiates were studied by both empirical and quantum mechanical methods. By both methods, conformers with maximum resemblance to rigid opiates have the highest energies. Conformers with the lowest energy had no resemblance to rigid opiates. However, several low and intermediate energy conformers were identified in which at least the NH2-terminal tyrosine residue overlaps with the phenethylamine moiety of rigid opiates and which could equally well accommodate either Gly2 or D-Ala2. The conformer among these with greatest additional resemblance to other binding sites of rigid opiates is proposed as the most likely candidate for an induced fit at the receptor site.

The interaction of a model anionic receptor site with a series of N-substituents of fused ring opiates have been characterized using the semi-empirical quantum chemical method, PCILO. The results are examined for their implications for induced opiate- receptor binding and agonist/antagonist activity.

Summary Conformational analysis has been performed on a series of 3R, 4R-4ϕ-piperidine analogues which have antagonist activity that is modulated by substituents at these positions rather than at the amine nitrogen. Analysis of the results obtained by the semi-empirical quantum mechanical method PCILO has led to a consistent hypothesis to explain the structure-activity profiles of these new opiates.

The optimized energies of seven beta-bends, repeating C5 and C7, and right- and left-handed alpha-helical conformations for each of eight tetrapeptides have been computed using empirical methods. Eight tetramers were selected: four helix-forming sequences with hydrophobic residues such as Val, Leu, Ile and Trp, and four helix-breaking sequences with hydrophilic residues such as Asp, Asn and Ser, as determined by their frequency of occurrence in beta turns in proteins. Analysis of the optimized conformations with energies less than or equal to 2.1 kcal/mol from the absolute minimum energy conformer for each tetramer reveals a correlation between low-energy conformations and those predicted from observed protein structures. These results show that energy calculations on small peptide fragments may be usefulin predicting protein structure.