Molecular dynamics study of substance P peptides in a biphasic membrane mimic

Two neuropeptides, substance P (SP) and SP-tyrosine-8 (SP-Y8), have been st udied by molecular dynamics (MD) simulation in a TIP3P water/CCl4 biphasic solvent system as a mimic for the water-membrane system. Initially, distanc e restraints derived from NMR nuclear Overhauser enhancements (NOE) were in corporated in the restrained MD (RMD) in the equilibration stage of the sim ulation, The starting orientation/position of the peptides for the MD simul ation was either parallel to the water/CCl4 interface or in a perpendicular /insertion mode. In both cases the peptides equilibrated and adopted a near -parallel orientation within similar to 250 ps. After equilibration, the co nformation and orientation of the peptides, the solvation of both the backb one and the side chain of the residues, hydrogen bonding, and the dynamics of the peptides were analyzed from trajectories obtained in the RMD or the subsequent free MD (where the NOE restraints were removed). These analyses showed that the peptide backbone of nearly all residues are either solvated by water or are hydrogen-bonded. This is seen to be an important factor ag ainst the insertion mode of interaction. Most of the interactions with the hydrophobic phase come from the hydrophobic interactions of the side chains of Pro-4, Phe-7, Phe-8, Leu-10, and Met-11 for SP, and Phe-7, Leu-10, Mel- ii and, to a lesser extent, Tyr-8 in SP-Y8, Concerted conformational transi tions took place in the time frame of hundreds of picoseconds. The concerte dness of the transition was due to the tendency of the peptide to maintain the necessary secondary structure to position the peptide properly with res pect to the water/CCl4 interface.