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

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 (epsilon = 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 (MID) simulations. could be classified into two energy minimized families: A and B, comprised of 64 (Pro C-gamma-endo orientation) and 19 (Pro C-gamma-exo orientation) structures. respectively. An examination of these families revealed the existence of a remarkably similar folded backbone conformation: torsion angles being phi(i+1) approximate to -65degrees, psi(i+1) approximate to 65degrees, phi(i+2) approximate to-65degrees, psi(i+2) approximate to -60degrees, characterizing a distorted type III beta-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 (HN+)-N-3... (COO-)-O-x 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-x-H...N-c 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. (C) 2002 Elsevier Science Ltd. All rights reserved.