Cyclic pentapeptides as models for reverse turns: Determination of the equilibrium distribution between type I and type II conformations of Pro‐Asn and Pro‐Ala β‐turns

Abstract

Cyclic pentapeptides are excellent models for reverse turns and have been used extensively in our laboratory to explore the influence of different amino acid sequences on turn preference. This paper is divided into two parts: In the first, we review our previous studies of cyclic pentapeptides. We summarize work that demonstrates the range of conformations possible within the cyclic pentapeptide backbone, the importance of sequence chirality in determining the backbone fold, and the utility of these cyclic pentapeptides as models for various turns. In the second, we present new results on two cyclic pentapeptides that contain beta-turns with Pro-Ala or Pro-Asn sequences in the i + 1 and i + 2 positions. By stereochemical criteria, a type I beta-turn is expected to be preferred by such L-L sequences. On the other hand, in proteins Asn occurs frequently in the i + 2 position of type II turns. We asked whether the same propensity would be manifest in an isolated model peptide, and if so, what the interactions were that influenced the relative stability of the type I and type II turns. To address these questions we have compared the conformational behavior of two peptides: cyclo(Gly-Pro-Ala-D-Phe-Pro) and cyclo(D-Ala-Pro-Asn-Gly-Pro). From previous studies, we anticipated that both peptides would contain an inverse gamma-turn and a beta-turn which consisted of either Gly-Pro-Ala-D-Phe or D-Ala-Pro-Asn-Gly in positions i to i + 3, respectively. Nuclear magnetic resonance analysis confirms this overall backbone conformation. Furthermore, quantitative nuclear Overhauser effect measurements in combination with molecular dynamics simulations and torsionally-forced energy minimizations have enabled us to determine that both type I and type II beta-turns are present in equilibrium in these peptides. The introduction of Asn in position i + 2 shifts this equilibrium significantly towards type II. We have done preliminary assessment of the possible side-chain/backbone conformations that contribute to the shift in populations.

Design, synthesis, and biological evaluation of scaffold-based tripeptidomimetic antagonists for CXC chemokine receptor 4 (CXCR4)

“…The linear precursors were prepared using either a preloaded Fmoc-Gly trityl resin (2, 5, and 10) or a 2-chlorotrityl chloride resin for the loading of the N-Fmoc ω-aminocarboxylic acids (6)(7)(8)(9). Cleavage from the resin was facilitated using hexafluoroisopropanol and the side-chain protected peptides were cyclized using PyBOP followed by global deprotection using TFA.…”

“…1,2 In addition to the developmental and physiological role of CXCL12/CXCR4, CXCR4 has been shown to be involved in a number of pathological conditions, including HIV, cancer, and rheumatoid arthritis. 3 Consequently, CXCR4 has emerged as an attractive drug target, and several smallmolecule CXCR4 antagonists have been described in the literature over the last decade, 3,4 including Small cyclic peptides, such as cyclopentapeptides, are known to mimic peptide turns, 6 i.e.…”

Methylation of the nuclear poly(A)-binding protein by type I protein arginine methyltransferases – how and why

“…As a test of this hypothesis, a pentapeptide containing a Pro-Arg sequence was tested as a PRMT1 substrate in a linear and in a cyclic form. The cyclization of short proline-containing peptides is known to stabilize reverse turns with the proline in the i + 1 position, thus putting the neighboring arginine into the i + 2 position (Pease and Watson , 1978 ;Holl ó si et al, 1987 ;Stradley et al , 1990 ;Kumaki et al , 2001 ). In fact, the cyclization of the pentapeptide led to a 15-fold increase in k cat and a 6-fold increase in k cat / K m for PRMT1-dependent methylation.…”

Conformations of Synthetic Model Peptides for Plasmodium falciparum Circumsporozoite Protein in Me2SO by 1H NMR and Distance Geometry Calculations

“…Even if they show characteristics of some secondary structure, they may exist as a mixture of conformational populations, including extended forms. 5 In order to see if the observed NOE cross-peaks and the hydrogen-bond information alone can produce any reasonable structure, we applied the distance geometry calculations to the present system without using the energy term. This is equivalent to searching a structure which satisfies all the NMR data but may not necessarily be energetically favorable.…”

“…4 Structural studies on cyclic model peptides have also shown that Pro-Asn combination promotes the formation of /)-turns especially in non-aqueous solvents. 5 In addition to the immunogenical importance, the above specific sequence is also of 1 To whom correspondence should be addressed.…”