Carrier design: conformational studies of amino acid (X) and oligopeptide (X-DL-Alam) substituted poly (L-lysine).

The present study was undertaken to examine the influence of the reversal of the side-chain sequential order on the conformation of branched polypeptides. At the same time, the influence of the optically active amino acid joined directly to the poly (L-Lys) backbone and the DL-Ala oligomer grafted as chain-terminating fragment were separately analyzed. Therefore two sets of polypeptides were synthesized corresponding to the general formula poly[Lys-(Xi)] (XK) and poly[Lys-(DL-Alam-Xi)] (AXK) when X = Ala, D-Ala, Leu, D-Leu, Phe, D-Phe, Ile, Pro, Glu, D-Glu, or His. For coupling amino acid X to polylysine, three types of active ester methods were compared: the use of pentafluorophenyl or pentachlorophenyl ester, and the effect of the addition of an equimolar amount of 1-hydroxy-benzotriazole. After cleavage of protecting groups, AXK polypeptides were synthesized by grafting short oligo(DL-Ala) chains to XK by using N-carboxy-DL-Ala anhydride. The CD measurements performed in water solutions of various pH values and ionic strengths were used for classification of the polypeptide conformations as either ordered (helical) or unordered. Different from what was observed with the unsubstituted poly (L-Lys), poly[Lys-(Xi)] type polypeptides can adopt ordered structure even under nearly physiological conditions (pH 7.3, 0.2M NaCl). These data suggest that the introduction of amino acid residue with either (ar) alkyl side chain (Ala, Leu, Phe) or negatively charged side chain (Glu) promotes markedly the formation of ordered structure. Comparison of chiroptical properties of poly[Lys-(DL-Alam-Xi)] and of poly[Lys-(Xi)] reveals that side-chain interactions play an important role in the stabilization of ordered solution conformation of AXK type branched polypeptides. The results give rather conclusive evidence that not only hydrophobic interactions, but also ionic attraction, can be involved in the formation and stabilization of helical conformation of branched polypeptides.