Molecular dynamics study of substance P peptides partitioned in a sodium dodecylsulfate micelle

Two neuropeptides, substance P (SP) and SP-tyrosine-8 (SP-Y8), have been st udied by molecular dynamics (MD) simulation in an explicit sodium dodecylsu lfate (SDS) micelle. Initially, distance restraints derived from NMR nuclea r Overhauser enhancements (NOE) were incorporated in the restrained MD (RMD ) during the equilibration stage of the simulation. It was shown that when SP-Y8 was initially placed in an insertion (perpendicular) configuration, t he peptide equilibrated to a surface-bound (parallel) configuration in simi lar to 450 ps. After equilibration, the conformation and orientation of the peptides, the solvation of both the backbone and the side chain of the res idues, hydrogen bonding, and the dynamics of the peptides were analyzed fro m trajectories obtained from the RMD or the subsequent free MD (where the N OE restraints were removed). These analyses showed that the peptide backbon es of all residues are either solvated by water or are hydrogen-bonded. Thi s is seen to be an important factor against the insertion mode of interacti on. Most of the interactions come from the hydrophobic interaction between the side chains of Lys-3, Pro-4, Phe-7, Phe-8, Leu-10, and Met-11 for SP, f rom Lys-3, Phe-7, Leu-IO, and Met-ii in SP-Y8, and the micellar interior. S ignificant interactions, electrostatic and hydrogen bonding, between the N- terminal residues, Arg-Pro-Lys, and the micellar headgroups were observed. These latter interactions served to affect both the structure and, especial ly, the flexibility, of the N-terminus. The results from simulation of the same peptides in a water/CCl4 biphasic cell were compared with the results of the present study, and the validity of using the biphasic system as an a pproximation for peptide-micelle or peptide-bilayer systems is discussed.