Equilibrium thermodynamic and kinetic estimations were used to confirm the rather unusual conformation, orientation, and accumulation of dynorphin A-(1-13)-tridecapeptide (dynorphin1-13) on the surface of neutral lipid membranes, as observed by Erne et al. [Erne, D., Sargent, D. F., and Schwyzer, R. (1985) Biochemistry 24, 4261-4263]. I started from the premise that the most stable conformation of molecularly disperse peptides in contact with the hydrophobic phase of a membrane is helical [Henderson, R. (1979) Soc. Gen. Physiol. Ser. 33, 3-15]. Calculation of the Gibbs free energy difference for the transfer of increasing numbers m of N-terminal residues of dynorphin1-13 from their random-coil conformation in water to their .alpha.-helical conformation in a hydrophobic phase, with the values provided by Von Heijne and Blomberg [Von Heijne, G., and Blomberg, C. (1979) Eur. J. Biochem. 97, 175-181], showed an energy minimum at m = 9 that corresponded to the observed apparent association constant of 9 .times. 104 L/mol. This confirmed our experimental observations. The orientation of dynorphin1-13 in the interphase was estimated by calculation of the molecular amphiphilic moment .vector.A. This force vector was defined in analogy to the "helical" and "structural" hydrophobic moments of Eisenberg at al. [Eisenberg, D., Weiss, R. M. and Terwilliger, T. C. (1982) Nature (London) 299, 371-374]. It takes into account the segregation of hydrophobic and hydrophilic residues with respect to the center of the .alpha.-helix. A peptide located in a hydrophobic-hydrophilic gradient experiences a torque that tends to orient .vector.A in a direction perpendicular to the surfaces of equal hydrophobicity. The scalar magnitude A is a measure for the tendency of a molecule to accumulate in the interphase (position of minimal energy of both its hydrophobic and hydrophilic domains). In dynorphin1-13, the direction of .vector.A was found to differ from that of the helix axis by only 11.degree.. Thus, the helix was expected to assume an almost perpendicular orientation on the membrane surface, which, again, agreed with the experiment. Rate considerations suggested that some of the initial collision complexes formed between peptide and membrane have lifetimes sufficiently long for the formation of short .alpha.-helices. Helix formation increases their lifetimes, and the initial helices become oriented in the interphase according to their .vector.A. This model is a plausible description of the events leading to the observed membrane interaction of dynorphin1-13.