Crystal structure and conformation of a cyclic tetrapeptide cyclo(L‐Pro‐Sar)₂ containing all‐cis peptide units

Abstract

SynopsisThe crystal structure and conformation of the synthetic cyclic tetrapeptide, cyclo(L-Pro-Sar)z, was determined by x-ray analysis. The peptide crystallizes in the orthorhombic space group P21212~ with cell parameters a = 9.277(1), b = 12.884(1), and c = 15.581(2) A. The crystal structure was solved by the symbolic addition procedure for direct phase determination and least-squares refinement using 1796 reflections, which led to the final R value of 0.043. This structure provides the first example observed in a crystal of a cyclic tetrapeptide in which all four peptide units have been found in the cis conformation with w angles deviating slightly by 2"-10" from the ideal value of 0". It was also found that the two Pro C"-CO single bonds assumed a trans' ($ = 159.6" and 158.4") conformation. Adjoining average planes of the peptide groups fall at nearly right angles to each other. The pyrrolidine ring conformations of the two prolyl residues are in the envelope form, with Cr carbon out of the least-squares planes for the remaining four atoms.

Cyclic tetrapeptides via the ring contraction strategy: chemical techniques useful for their identification

“…X-ray structures of cyclic tetrapeptides indicate that the x angles (Ca-CO-NH-Ca torsion angles) are quite commonly twisted from planarity, regardless of whether the amide bonds are cis or trans. 12,13,15-18, 33 In fact, the all-trans cyclic tetrapeptides commonly possess a x angle twist of ± 15-25 • . 3,5,12, 13 As a result, all of the energy restraints in parallhdg5.2.pro (the X-PLOR parameter file) on the x torsion angle were relaxed from their default value of 500.…”

Understanding and designing head‐to‐tail cyclic peptides

“…For example, cyclic tripeptides are generally highly strained and contain at least one cis peptide bond, with the most energetically favorable conformation consisting of three cis peptide bonds . Cyclic tetrapeptides are the smallest CPs that can adopt an all‐ trans conformation, although they generally adopt either an all‐ cis or alternating cis / trans conformation …”

“…Arguably the most significant challenge in CP design is our poor understanding of their sequence–structure relationships. The current majority of experimental structural information for small CPs (≤8 amino acids) comes from X‐ray crystal structures and NMR structures in organic solvent . However, X‐ray crystal structures lack dynamic information, providing only a single snapshot among a possible ensemble of structures available in solution.…”

Further C‐Alkylations of Cyclotetrapeptides via Lithium and Phosphazenium (P4) Enolates: Discovery of a New Conformation

“…Other conformations are seen far less frequently. A cccc arrangement has been found for cyclo(-Pro-Sar-Pro-Sar-) in the solid state [38] and in (D,)DMSO [39]. Studies of equilibrium mixtures have led to the observation of a ccct conformation [27] [39] and a cctt orientation has also been suggested [24].…”

“…phase was dried (MgS04) and evaporated and the residue purified by FC (AcOEt/hexane 3:l). J=18,1H);3.20,3.00(2s,3H);2.90(s,3H);1.75(m,1H);1.55-1.25(m,14H);1.00,0.90,0.85(dorm,J=8, 6 H (38), 57 (100).…”