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A new amino acid has been designed as a replacement for arginine (Arg, R) to protect the tumor-homing pentapeptide CREKA (Cys-Arg-Glu-Lys-Ala) from proteases. This amino acid, denoted (Pro)hArg, is characterized by a proline skeleton bearing a specifically oriented guanidinium side chain. This residue combines the ability of Pro to induce turn-like conformations with the Arg side-chain functionality. The conformational profile of the CREKA analogue incorporating this Arg substitute has been investigated by a combination of simulated annealing and molecular dynamics. Comparison of the results with those previously obtained for the natural CREKA shows that (Pro)hArg significantly reduces the conformational flexibility of the peptide. Although some changes are observed in the backbone···backbone and side-chain···side-chain interactions, the modified peptide exhibits a strong tendency to accommodate turn conformations centered at the (Pro)hArg residue and the overall shape of the molecule in the lowest energy conformations characterized for the natural and the modified peptides exhibit a high degree of similarity. In particular, the turn orients the backbone such that the Arg, Glu, and Lys side chains face the same side of the molecule, which is considered important for bioactivity. These results suggest that replacement of Arg by (Pro)hArg in CREKA may be useful in providing resistance against proteolytic enzymes while retaining conformational features which are essential for tumor-homing activity. [ABSTRACT FROM AUTHOR]

Quantum mechanical calculations have been used to investigate how the incorporation of an amino group to the C β- or C γ-positions of the pyrrolidine ring affects the intrinsic conformational properties of the proline. Specifically, a conformational study of the N-acetyl- N′-methylamide derivatives of four isomers of aminoproline, which differ not only in the β- or γ-position of the substituent but also in its cis or trans relative disposition, has been performed. To further understand the role of the intramolecular hydrogen bonds between the backbone carbonyl groups and the amino side group, a conformational study was also performed on the corresponding four analogues of (dimethylamino)proline. In addition, the effects of solvation on aminoproline and (dimethylamino)proline dipeptides have been evaluated using a self-consistent reaction field model, and considering four different solvents (carbon tetrachloride, chloroform, methanol and water). Results indicate that the incorporation of the amino substituent into the pyrrolidine ring affects the conformational properties, with backbone···side chain intramolecular hydrogen bonds detected when it is incorporated in a cis relative disposition. In general, the incorporation of the amino side group tends to stabilize those structures where the peptide bond involving the pyrrolidine nitrogen is arranged in cis. The aminoproline isomer with the substituent attached to the C γ-position with a cis relative disposition is the most stable in the gas phase and in chloroform, methanol and water solutions. Replacement of the amino side group by the dimethylamino substituent produces significant changes in the potential energy surfaces of the four investigated (dimethylamino)proline-containing dipeptides. Thus, these changes affect not only the number of minima, which increases considerably, but also the backbone and pseudorotational preferences. In spite of these effects, comparison of the conformational preferences, i.e., the more favored conformers, calculated for different isomers of aminoproline and (dimethylamino)proline dipeptides showed a high degree of consistency for the two families of compounds. [ABSTRACT FROM AUTHOR]

The intrinsic conformational preferences of proline analogues having double bonds between carbon atoms in their rings have been investigated using quantum mechanical calculations at the B3LYP/6-31G(d,p) level. For this purpose, the potential energy surface of the N-acety-N‘-methylamide derivatives of three dehydroprolines (proline analogues unsaturated at ,; ,; and ,) and pyrrole (proline analogue with unsaturations at both , and ,) have been explored, and the results are compared with those obtained for the derivative of the nonmodified proline. We found that the double bonds affect the ring puckering and the geometric internal parameters, even though the backbone conformation was influenced the most. Results indicate that the formation of double bonds between carbon atoms in the pyrrolidine ring should be considered as an effective procedure to restrict the conformational flexibility of prolines. Interestingly, we also found that the N-acetyl-N‘-methylamide derivative of pyrrole shows a high probability of having a cis peptide bond preceding the proline analogue. [ABSTRACT FROM AUTHOR]