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ABSTRACT Molecular dynamics simulations have been performed of the sequence-symmetric cyclic decapeptide antibiotic gramicidin S (GS), in interaction with a hydrated dimyristoylphosphatidylcholine (DMPC) bilayer, and the results compared with a "control" simulation of the system in the absence of GS. Following experimental evidence, the GS was initially set in a single antiparallel 0-sheet conformation with two Type I1' E-turns in an amphiphilic interaction with the membrane. This conformation and position remained in the 6.5 ns simulation. Main-chain dihedrals are on average -26 from those determined by NMR experiment on GS in dimethylsulfoxide (DMSO) solution. Sequence-symmetric main-chain and sidechain dihedral angle pairs converge to within -50 and -10, respectively. The area per lipid, lipid tail order parameters, and quadrupole spin-lattice relaxation times of the control simulation are mostly in good agreement with corresponding experiments. The GS has little effect on the membrane dipole potential or water permeability. However, it is found to have a disordering effect (in agreement with experiment) and a fluidifying effect on lipids directly interacting with it, and an ordering effect on those not directly interacting.
INTRODUCTION
There is much interest in understanding the interaction of peptides with lipid bilayers at atomic detail. This requires characterization of the position, orientation, structure, and dynamics of the peptide in the lipid bilayer and its effects on surrounding lipids. Although molecular dynamics (MD) simulation can in principle furnish complete structural and dynamical information, considerable obstacles exist to obtaining accurate results, due partly to inexact force fields and other approximations in simulation methodology, and partly to the relaxation times of some important dynamical phenomena being of the order of or longer than those presently accessible to MD.
Gramicidin S, [cyclo-(Leu-D-Phe-Pro-Val-Orn)2, (GS)] is a cyclic decapeptide that is of particular interest for pursuing peptide/membrane MD studies. The sequence and structure of the peptide are relatively simple. NMR, x-ray, and MD studies indicate that the backbone adopts an antiparallel )3-sheet with two Type II' 13-turns in various solutions of different polarity and in the crystalline form (Jones et al., 1978; Hull et al., 1978; Mihailescu and Smith, 1999). One consequence of this is that the GS structure is amphipathic, with the hydrophobic side chains on one side of the molecule and the hydrophilic ones on the other, and...