Folded conformation of an immunostimulating tetrapeptide rigin: high temperature molecular dynamics simulation study.

Abstract Employing high temperature quenched molecular dynamics (QMD) simulations the conformational energy space of an immunostimulating tetrapeptide rigin: H-Gly 341 -Gln-Pro-Arg 344 -OH, is explored. Using distance dependent dielectric (e= r ij ) 31 different low energy starting structures with identical sequence were computed for their conformational preferences. According to the hypothesis of O'Connors et al. [ J. Med. Chem. 35 (1992), 2870], 83 low-energy conformers resulted from unrestrained molecular dynamics (MD) simulations, could be classified into two energy minimized families: A and B , comprised of 64 (Pro C γ - endo orientation) and 19 (Pro C γ - exo orientation) structures, respectively. An examination of these families revealed the existence of a remarkably similar folded backbone conformation: torsion angles being φ i +1 ≈−65°, ψ i +1 ≈−65°, φ i +2 ≈−65°, ψ i +2 ≈−60°, characterizing a distorted type III β-turn structure across the central Gln-Pro segment. The folded conformation of rigin is devoid of a classical 1 ← 4 intra-molecular hydrogen bond nevertheless, the conformation is stabilized by an effective ‘ salt-bridge ’, i.e., Gly H 3 N + … C α OO − Arg interaction. Surprisingly, in both the families the unusual folded side-chain dispositions of the Gln residue favor the formation of a unique intra-residue ‘main-chain to side-chain’ H-bond, i.e., N α –H…N ϵ interaction, encompassing a seven-membered ring motif. The conformational attributes may be valuable in de novo construction of structure-based drug candidates having sufficient stimulating activity.