Replacement of Phe(8) in substance P by Tyr (Tyr(8)-SP) alters the conformation of the peptide in DMSO, water, and lipid bilayers

The conformation of [Tyr(8)]SP (Y8SP) in dimethylsulfoxide (DMSO), water an d dipalmitoyl phosphatidylcholine (DPPC) bilayers has been investigated by two-dimensional nmr and molecular dynamics simulations. Molecular modeling of the conformation of Y8SP by incorporating nuclear Overhauser effects as distance restraints shows wide differences in its conformation in the three media. In DMSO, the main structural features are gamma-bends along with a nonspecific bend around Gln(6)-Phe(7)-Tyr(8). The random coil structure see n irt water is transformed into a beta-turn around the segment Gln(5)-Gln(6 )-Phe(7)-Tyr(8) when Y8SP is incorporated into DPPC bilayers. The lower bio logical activity of Y8SP compared to the native peptide (SP) has been attri buted to the absence of any helix like structure at the central residues, a feature shown to be an important prerequisite for SP and SP agonists to bi nd to the neurokinin I tachykinin receptor. (C) 1999 John Wiley & Sons, Inc .