Conformation and formation tendency of the cyclotetrapeptide cyclo(D‐pro‐D‐pro‐L‐pro‐L‐pro): Experimental results and molecular modeling studies

Abstract

The title compound represents the smallest member of cyclic proline peptides corresponding to the general formula c(DDLL-Pro4)n with a strictly D,D,L,L double-alternating sequence of the chiral amino acid residues. The cyclopeptides with n greater than or equal to 2 could be synthesized from both DDLL-Pro4 (1) and DLLD-Pro4 (2). The cyclic monomer (n = 1) resulted only from 2, whereas not even a trace could be found by cyclization of 1. The peptide exists in a strongly strained Ci symmetrical conformation (x-ray analysis) with alternating cis and trans peptide bonds (ctct form I). The cis peptide bonds deviate from planarity (omega = 22 degrees); two of the pyrrolidine rings show a "South" conformation (phi = -94 degrees), whereas the other residues exhibit C alpha-endo puckering (phi = -124 degrees). Two of the psi angles surprisingly occur at +41 degrees (anti-cis'), the others are located in the trans' region. A quantitative ring opening occurs with trifluoroacetic acid at room temperature. In solution the existence of an isomeric ctcc sequence (form Ia) is indicated. Dreiding model studies also suggested a favorable conformation with a tctc sequence (form II). Consequently, we performed molecular mechanics calculations, based on the CHARMM force field and semiempirical quantum mechanical AM1 calculations (MOPAC program). Pronounced differences in the backbone parameters were found using these two methods. However, the theoretical studies evidenced the experimentally obtained differences in the cyclization tendencies of the linear precursors.

Cyclization of Linear Tetrapeptides Containing N‐Methylated Amino Acids by using 1‐Propanephosphonic Acid Anhydride

“…This indicated that 6a and 6b , presumed to be cyclic peptides, were hydrolyzed. While the ring opening of cyclotetrapeptides has been reported to occur under relatively mild hydrolytic conditions [TFA/H 2 O (8:2), 5 h, r.t.],[15a] there is no precedent for cyclotetrapeptides to undergo ring opening under slightly acidic conditions such as those used in RP‐HPLC (mobile phase consisted of 0.1 % TFA in H 2 O/MeCN mixtures). Furthermore, attempts to isolate 6a and 6b either by RP‐HPLC under neutral conditions or by silica‐gel chromatography failed, even if the purification was performed at low temperatures (e.g., 5 °C).…”

“…Moreover, even for linear peptides containing several turn‐promoting amino acids, the success of cyclization is still sequence dependent . For instance, the cyclo( d Pro‐ d Pro‐Pro‐Pro) peptide can only be obtained upon starting from H‐ d Pro‐Pro‐Pro‐ d Pro‐COOH …”

Conformational study of linear alternating and mixed D‐ and L‐proline oligomers using electronic and vibrational CD and fourier transform IR

“…Alternatively, DLDLDL-Pro6 cyclizes at high dilution ( < 0.00 1 M ) with -80% yield of the hexaprolyl ring and 9% dimer; but at 0.0 1 M concentration, the monomer yield decreases to 3%, with 7% dimer and more than 70% of polymeric material. 23 The low yield of oligomeric ring formation at moderate concentration can be ascribed to a relatively stable helical conformation of the linear intermediates.…”

Study on the cyclization tendency of backbone cyclic tetrapeptides

“…Recent advances in the area of structural modeling have increased our ability to design bioactive cyclic peptides and peptidomimetics, yet the cyclization step in the actual synthesis is often troublesome, particularly for head‐to‐tail cyclization of small (< 7 residues) peptides (5). Several cases have been reported in the literature in which cyclization yields depend strongly on the sequence of the linear peptide precursor (5–9). Moreover, several linear precursors, all leading to the same cyclic product, often showed highly variable yields in the cyclization (7–9).…”

“…Several cases have been reported in the literature in which cyclization yields depend strongly on the sequence of the linear peptide precursor (5–9). Moreover, several linear precursors, all leading to the same cyclic product, often showed highly variable yields in the cyclization (7–9).…”