SOLUTION CONFORMATION OF A CYCLIC NEUROKININ ANTAGONIST - A NMR AND MOLECULAR-DYNAMICS STUDY

The solution structure of a hexapeptide, cyclo(Gln-Trp-Phe-GLy-Leu-Met ), which is a selective NK-2 antagonist, has been studied by a combina tion of two-dimensional nmr and molecular dynamics (MD) techniques. Th e simulation based on nmr and MD data resulted in the convergence to a family of structures. Free molecular dynamics for 50 ps in the presen ce of DMSO solvent molecules shows that the structure is energetically stable. One intramolecular hydrogen bond between the amide proton of Gln and the carbonyl oxygen of Gly was revealed. This result is consis tent with the results from the measurement of the temperature coeffici ent of the amide protons. The extent of intermolecular hydrogen bondin g between the amide protons of the peptide and DMSO was also revealed by the free MD simulation. The resulting structure of the cyclic pepti de contains a variation type I' beta-turn in the Gly-Leu-Met-Gln segme nt. Comparison of the structure of this peptide with that of other NK- 2 antagonist cyclic hexapeptides was made, and the activity of cyclic antagonists appears to be inversely related to the conformational rigi dity of the cyclic peptides. (C) 1994 John Wiley & Sons, Inc.