New insight in the structural characterization of turns in peptides: determination of NMR discriminatory parameters
Résumé
During the last decades, there has been an increased interest in the use of peptides as therapeutics. The knowledge of the 3D structure of these molecules is crucial to gain a full understanding of their structure-activity relationships and to identify the motifs involved in partner recognition and binding[1]. Peptide flexibility makes solution NMR coupled to molecular modelling the privileged method for structural studies.
It has been shown that helices and turns constitute the preferential recognition patterns of bioactive peptides by their targets. Despite their prevalence, turns have always been more challenging to characterize by NMR than alpha-helices, because of their non-periodic nature and their heterogenic structures. Indeed, several classes of turns, characterized by a different number of residues and exhibiting different geometries, exist in polypeptide structure. In the literature, the establishment of the NMR characteristic data (H-H distances and scalar couplings) of these different structural motifs is based on a rather ancient analysis of poly-alanine chains[2], which does not take into account all the types of turns or the influence of the nature of the side-chain on these structures.
The aim of this work is to provide additional and new structural information, via molecular modelling calculations, to better characterized each type of turns. We focused on beta-turns (4 residues) and gamma-turns (3 residues), which are the most encountered turns in peptide structures.
Specific H-H distances were measured in a set of turns selected from PDB X-ray protein structures. New characteristic signatures that permit to identify, by NMR, all types of beta-turns and of gamma-turns were found. Particular attention has been paid to the proline structural role in these secondary structures.
To complete the analysis, the 3JHN-Halpha scalar coupling constant of the central residue of gamma-turns or the two central residues of beta-turns was calculated[3], [4]. For most of the beta-turns, the set of coupling constants allowed to discriminate one turn from another.
Taken together, signatures allowing to discriminate all types of beta-turns and gamma-turns by different distances and scalar coupling constants were established. These new data will enable to refine the NMR structural description of turns in peptides and might be applied to peptidomimetic studies.
References
1.J. A. Robinson Acc. Chem. Res. (2008), 41, 1278-1288
2.K. Wüthrich, M. Billeter and W. Braun J. Mol. Biol. (1984), 180, 715-740
3.S. Ludvigsen, K. V. Andersen and F. M. Poulsen J. Mol. Biol. (1991), 217, 731-736