Gastrin-Releasing Peptide Adopts An Orientation Parallel To The Membrane Plane As A Preferred Orientation In DMPC Bilayers: Multiple Molecular Dynamics Simulations

Abstract

Gastrin-releasing peptide (GRP) binds to GRP-receptor (GRPR), a member of GPCR family. GRP is one of the bombesin peptides and they are implicated in obesity and cancer. Understanding the mechanism of GRP-GRPR interactions at molecular level is extremely significant and requires the knowledge of the structure of peptide-receptor complex. Since the complex structure is not available, the structures of ligand and the free receptor could be used to model the complex. GRP is flexible in aqueous medium but it is likely to adopt a stable structure when it binds to membrane according to “Membrane Compartments Theory” [Biopolymers 37, 5-16 (1995)]. The C-terminal decapeptide of GRP is biologically active and is modeled as a helix using a related peptide structure determined in SDS micelles [FEBS Lett. 460, 263-269 (1999)]. Its amino acid sequence is GNHWAVGHLM. We carried out multiple independent simulations of GRP peptide in explicit DMPC bilayers which differed in the orientation of GRP inside the bilayers and force-field. At the end of 10 to 20 ns production runs, five out of six simulations resulted in the peptide orientation that is nearly parallel to the membrane plane. This indicates that this orientation is a preferred one and is independent of CHARMM or GROMOS force-fields. In the sixth simulation, the peptide was deeply inserted inside the bilayer. We analyzed the stability of helix, interaction of individual residues with different lipid components and water penetration in both layers. The helix structure is stable in majority of the simulations. Our results indicate that the residues Gly-7 and His-8 are important in maintaining the helical structure and orienting the peptide. We thank CSIR for financial support [No. 37(1199)/04/EMR-II].