There is still a significant gap in our understanding of the physicochemical properties of membrane systems with embedded peptides. This limits the ability to understand key biological mechanisms of systems in which the effects of peptides and small proteins are determined by their environment. In previous studies of the 17-residue endogenous opioid peptide dynorphin A [(Dyn Aft - 17)], a selective ligand Of kappa-opioid receptors that is important as an analgesic, we have shown from molecular dynamics (MD) simulations in dimyristoylphosphatidyleholine (DMPC) that the peptide maintains a defined secondary structure and a characteristic position within the membrane bilayers (Sankararamakrishnan and Weinstein, Biophys. J. 2000, 79, 2331-2344). Because some fragments of Dyn A(1-17) have cognate pharmacological properties, we studied the behavior of the smaller opioid [Dyn A(1 - 13)] and the nonopioid fragment of dynorphin [des-Tyr dynorphin; Dyn A(2-17)] in DMPC bilayers with MID simulations for periods of 9 and 6.5 ns, respectively. Dyn A(1 - 13) was found to behave similarly to the full length peptide Dyn A(I - 17) in the bilayer. Its N-terminal helical segment that was initially oriented perpendicular to the membrane plane remained imbedded within the bilayers throughout the simulations and adopted a tilt angle of similar to35degrees with respect to the bilayer normal. Analysis of the peptide-membrane interactions reveals the key role of arginine and lysine residues which, as in Dyn A(1-17), are organized structurally in "snorkel-model" type bonding and contributed significantly toward peptide-DMPC and peptide-water interaction energies. In contrast, the absence of tyrosine in Dyn A(2-17) is found to yield (a) deeper membrane penetration of the helical segment and (b) a smaller extent of water penetration into the bilayers. The positioning of both Dyn A(I - 17) and Dyn A(I - 13) is determined by interactions of the aromatic residues tyrosine and phenylalanine, which are shown to prefer different components of the lipid bilayers. The nature of the dramatic differences in the mode of interactions with the membrane observed for the des-Tyr congener suggests a general mechanistic role for Tyr and Phe residues in determining both the physicochemical and the biological properties of peptides in the membrane environment. The importance of this role is illustrated by Tyr-1. We show that this residue is keeping the pharmacologically active Dyn A(1 - 17) peptide close to the membrane-water interface, a position that may be a determinant factor in the binding mechanism of the peptide with opioid receptors.