Relationship between conformation and physicochemical properties of polypeptides. I. Synthesis of homo‐ and co‐oligopeptides by the liquid‐phase method

Abstract

AbstractThe synthesis of the following oligo‐ and co‐oligopeptides by the liquid‐phase method is described: (L‐Met)15 (I), [L‐Glu(OBzl)]20 (II), (L‐Val)8‐Gly (IV), (L‐Ile)8‐Gly (V), (L‐Ile)4‐Gly‐(L‐Ile)4 (VI), (L‐Ile)4‐Pro‐(L‐Ile)4 (VII), (L‐Met)5‐L‐Pro‐(L‐Met)5 (VIII), [L‐Glu(OBzl)]7‐L‐Pro‐[L‐Glu(OBzl)]7 (IX). The oligomers are covalently bound to bifunctional polyethylene glycol (PEG) and monofunctional PEG‐M of Mr 5 × 103−2 × 104. Analytical controls were carried out after each step of synthesis in order to ensure quantitative coupling yields. All products could be obtained in high purity as indicated by amino acid analysis, thin‐layer chromatography and chiroptical methods. The solubility of the oligomers was strongly enhanced by the presence of the C‐terminal PEG group, enabling conformational investigations in a variety of solvents. A significant relationship between conformation and physicochemical properties of the oligopeptides was observed. Oligomers with tendencies to adopt α‐helical (I, II) or unordered structures (VI–IX) showed no pronounced change in solubility or coupling kinetics during chain elongation, whereas the onset of a β‐structure (IV, V) was paralleled by a drastic decrease in solubility and reactivity of the terminal amino groups. Most notably, the insertion of a proline or glycine in the middle of a β‐forming peptide chain (VI, VII) resulted in a considerable increase in solubility compared to the corresponding homo‐oligomers. The impact of the conformational properties of a peptide chain on strategic considerations of peptide synthesis in solution is delineated.