COMPARED STRUCTURES OF THE FREE NICOTINIC ACETYLCHOLINE-RECEPTOR MAINIMMUNOGENIC REGION (MIR) DECAPEPTIDE AND THE ANTIBODY-BOUND [A(76)]MIR ANALOG - A MOLECULAR-DYNAMICS SIMULATION FROM 2-DIMENSIONAL NMR DATA

Monoclonal antibodies against the main immunogenic region (MIR) of the muscle acetylcholine receptor (AChR) are capable of inducing experime ntal myasthenia gravis (MG) in animals. The epitope of these antibodie s has been localized between residues 67 and 76 of the AChR cu-subunit . The conformation in solution of the Torpedo californica MIR peptide and of its [A(76)] MIR analogue have been analyzed using molecular mod eling based on nmr interproton distances and J-derived phi dihedral an gles. Molecular dynamics simulations including dimethyl-sulfoxide as e xplicit solvent have been carried out on the free MIR peptide. Calcula tion of the structure of the [A(76)]MIR analogue bound to an anti-MIR monoclonal antibody have been performed in the presence of water molec ules. A tightly folded structure appears for bothpeptides with a beta- folded N-terminal N-68-P-A-D-71 sequence of type I in the free state a nd type III in the mAb6-bound state. The C-terminal sequence is folded in two different ways according to the result in the free and bound s tate of the peptides: two overlapping beta/beta ar beta/alpha turns re sult in a short helical sequence in the free MIR peptide, whereas the bound analogue is folded by an uncommon hydrogen bond closing an 11-me mbered, cycle. This structural evolution is essentially the result of the reorientation of the hydrophobic side chains that are probably dir ectly involved in peptide-antibody recognition. (C) 1997 John Wiley & Sons, Inc.