Characterization of a novel type VII β‐turn conformation for a bio‐active tetrapeptide rigin

Abstract

The conformational analysis of an immunomodulating tetrapeptide rigin (H-Gly-Gln-Pro-Arg-OH), shown to possess diverse immunological activity, has been investigated both theoretically and experimentally for its conformational preferences. Unrestrained molecular dynamics simulation studies in implicit dimethylsulfoxide provide strong support for the existence of a significant population of ordered reverse turn structures for the major trans isomer. Of the three different energy minimized families, generated from computer molecular modelling, only one could be complemented by most of the 1D and 2D 1 H NMR parameters obtained in dimethylsulfoxided 6 . A variable temperature NMR experiment in dimethylsulfoxide-d 6 revealed that the preferred conformation is not stabilized by an intramolecular hydrogen bonding interaction. An analysis of the 2D ROESY experiment provides evidence in favour of an uncommonly observed, rather ill-defined type VII b-turn structure. A survey of the observed specific inter-and intra-residue NOE connectivities and their comparison with one of the predicted low-energy conformations, demonstrates synergy between the theoretical molecular modelling and experimentally determined NMR spectral data. The primary structure, rather than long-range interactions, appears to be critical in determining the folding behaviour of the bio-active rigin. The present structural attributes may be valuable in peptide drug design and development of the rigin analogs having more effective stimulating activity.

A putative bioactive conformation for the altered peptide ligand of myelin basic protein and inhibitor of experimental autoimmune encephalomyelitis [Arg91, Ala96] MBP87–99

“…The first set of dynamics was completely unrestrained (I) [32], using a sampling period of 5 ps. Two sets of backbone restrained dynamics were performed, using a sampling period of 2 ps.…”

Conformational Analysis of Ac-NPGQ-NH2 and Ac-VPaH-NH2 by Vibrational Circular Dichroism Spectroscopy Combined with Molecular Dynamics and Quantum Chemical Calculations

“…Also, they are small enough to allow easy optimization of the parameters of computational methods applied. MD simulations are widely used for conformational studies and were applied previously for particular sequences which incorporate -turn structure [23][24][25][26][27][28][29][30][31]. VCD spectral characteristics of -turns has been studied and identified in linear [32][33] and disulfide-cyclized [32] tetrapeptides and longer natural [34][35][36] and model [33,37] sequences.…”

Determination of an unusual secondary structural element in the immunostimulating tetrapeptide rigin in aqueous environments: insights via MD simulations, 1H NMR and CD spectroscopic studies

“…Gly H 3 N + ···COO − Arg interaction 12. Also, we established a synergy between the high‐temperature MD simulations in implicit DMSO and 1D and 2D 1 H NMR‐derived parameters acquired in DMSO‐d 6 solution 10, 11. It may be emphasized that MD simulations with implicit solvent models have become an established tool to analyze biomolecular structures and dynamics, complementary to experimental techniques, and gained widespread acceptance 18–20.…”

“…Phase‐sensitive 2D TOCSY and NOESY experiments were carried out using time proportional phase increments, with the carrier on the water resonance for its presaturation. Water suppression parameters, the spin lock power setting and the mixing time delay of 200 ms, were used as justified and described previously 5, 11. The number of data points acquired along t 1 and t 2 were 256 × 1024, respectively.…”

“…The two immunomodulators may be considered similar but not identical and such closely related peptide sequences provide excellent biological probes to elucidate biological processes for understanding their specific functions in living systems. Despite undoubted therapeutic potential utility of these immunomodulators, only limited reports exists in respect of rigin's structure–function relationships 2, 4, 10–12. Although the chemical identity of rigin has been described more than three decades ago, unlike with tuftsin 13, 14, no attempt has been made to identify and characterize the rigin receptor.…”