Removing the C-terminal protecting group enlarges the crystal size: Z–(Gly–Aib)₂–OH·H₂O

Abstract

The achiral tetrapeptide monohydrate N-(benzyloxycarbonyl)glycyl-α-aminoisobutyrylglycyl-α-aminoisobutyric acid monohydrate, Z–Gly–Aib–Gly–Aib–OH·H2O (Z is benzyloxycarbonyl, Aib is α-aminoisobutyric acid and Gly is glycine) or C20H28N4O7·H2O, exhibits two conformations related by the symmetry operation of an inversion centre. It adopts only one of two possible intramolecular hydrogen bonds in a type I (and I′) β-turn and forms a maximum of intermolecular hydrogen bonds partly mediated by water. The space group, the molecular structure and the crystal packing differ from two already described (Gly–Aib)2 peptides which vary only in the protecting groups. This structure confirms the high structural flexibility of Gly–Aib peptides and points to a strong relationship between intermolecular hydrogen bonding and crystal quality and size.

Z-Ala–Ile-OH, a dipeptide building block suitable for the formation of orthorhombic microtubes

“…These interactions enhance a close packing of the molecules, which is reflected by the relatively high crystal density of 1.258 Mg m À 3 in comparison with other peptide structures without cocrystallized solvent molecules. A relationship between close packing, high crystal density and suitable crystal size for X-ray analysis was observed recently (Gessmann et al, 2020). A search for related structures and their ability to form nanoparticles in the Cambridge Structural Database (CSD; Groom et al, 2016) revealed the Ala-Gly-OH, Ala-Ala-OH and Ala-Val-OH dipeptides (Houton et al, 2012).…”

The first non‐helical Aib‐containing hexapeptide: The crystal structure of Z‐Gly‐Aib‐Gly‐Aib‐Gly‐Aib‐OtBu

“…To Z‐(Gly‐Aib) 2 ‐OH A (3.82 g, 8.75 mmol; see Gessmann et al 13 ) and HOBt × H 2 O, approximately 20% (2.36 g), dissolved in dichloromethane (30 ml), water soluble carbodiimide, EDC × HCl (1.85 g, 9.63 mmol) was added with stirring. After 1 h at ambient temperature, a solution of H‐Gly‐Aib‐O t Bu B (2.08 g, 9.63 g; see 12 ) in dichloromethane (10 ml) was added.…”

“…Yield 4.56 g (82.3%) of a powder composed of clusters of extremely fine white needles providing a single spot after visualization on silica gel TLC plates. For the synthesis of A and B , see Gessmann et al 13 The powder of Z‐(Gly‐Aib) 3 ‐O t Bu proved almost insoluble even in hot methanol. In order to obtain single crystals suitable for crystallography experiments, a sample of the peptide was dissolved in hot ethyl acetate and crystallized by the addition of small amounts of n ‐hexane.…”

“…Z‐Gly‐Aib‐Gly‐Aib‐OH adopts fully extended conformation in the first residue, helical values in residues 2 and 3, and is in semi‐extended conformation in the fourth residue. One β‐turn is formed with a hydrogen bond between the first and the fourth residues 13 . H‐Gly‐Aib‐Gly‐Aib‐O t Bu starts at the N‐terminus with two residues in one helical region and changes the sense of the handedness for the two others.…”