Membrane Structure of Substance P. I. Prediction of Preferred Conformation, Orientation, and Accumulation of Substance P on Lipid Membranes

Preferred conformation, orientation, and accumulation of substance P on a neutral hydrophilic‐hydrophobic interface was estimated and extrapolated to interactions with neutral and anionic lipid bilayer membranes according to our general procedure. Nine residues at the C‐terminus were predicted to be transferred to the hydrophobic phase as an α‐helical domain, oriented quite perpendicularly on the membrane surface. The N‐terminal residues remained in the aqueous phase with their charges exposed to H2O. The molecular amphiphilic moment vector was strong (338 arbitrary units) and pointed its hydrophilic end towards the N‐terminus, only 15° away from the helix axis. The molecular electric dipole moment vector was also strong (124 debye) and pointed its positive end towards the N‐terminus, only 9° away from the helix axis. Thus, it reinforced the effect of the amphiphilic moment of a peptide intruding into the membrane dipole layer. The estimated dissociation constant for the equilibrium between membrane‐bound and free substance P was Kd ≈︁ 46 mM for neutral membranes, and Kd ≈︁0.43 mM for anionic membranes with a Gouy‐Chapman surface potential of −40 mV. Thus, substance P behaved similarly to dynorphin A and adrenocorticotropin peptides which insert their N‐terminal message segments as perpendicularly oriented helical domains into membranes, whereas their C‐terminal address segments remain in the aqueous phase as random coils. Substance P is the first instance of a neuropeptide which is expected to insert a C‐terminal message into lipid membranes.