Compared structures of the free nicotinic acetylcholine receptor main immunogenic region (MIR) decapeptide and the antibody-bound [A76] MIR analogue: A molecular dynamics simulation from two-dimensional NMR data

✍ Scribed by Piotr Orlewski; Michel Marraud; Manh-Thong Cung; Vassilios Tsikaris; Maria Sakarellos-Daitsiotis; Constantinos Sakarellos; Efstratia Vatzaki; Socrates J. Tzartos

• Publisher: Wiley (John Wiley & Sons)
• Year: 1996
• Tongue: English
• Weight: 977 KB
• Volume: 40
• Category: Article
• ISSN: 0006-3525
• DOI: 10.1002/(sici)1097-0282(1996)40:5<419::aid-bip1>3.0.co;2-z

✦ Synopsis

Monoclonal antibodies against the main immunogenic region (MIR) of the muscle acetylcholine receptor (AChR) are capable of inducing experimental myasthenia gravis ( M G ) in animals. The epitope of these antibodies has been localized between residues 67 and 76 of the AChR a-subunit. The conformation in solution of the Torpedo californica MIR peptide and of its [A76]MIR analogue have been analyzed using molecular modeling based on nmr interproton distances and J-derived 4 dihedral angles. Molecular dynamics simulations including dimethylsulfoxide as explicit solvent have been carried out on the free MIR peptide. Calculation of the structure of the [A7']M1R analogue bound to an anti-MIR monoclonal antibody have been performed in the presence of water molecules. A tightly folded structure appears for both

Correspondence to: Mad-Thong Cung Contract grant sponsor: The Association FranGaise centre les Myopathies, the CNRS, BIOMED program of EU, and the HCM program of EU Contract grant number: CT93-1100 (BIOMED) and CT94-0547 (HCM) 0 1997 John Wiley & Sons, Inc. CCC 0006-3525/97/0504 19-14 419

peptides with a P-folded N-terminal NhX-P-A-D7' sequence of type I in the free state and 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 state of the peptides: two overlapping PIP or p l a turns result in a short helical sequence in the free MIU peptide, whereas the bound analogue is folded by an uncommon hydrogen bond closing an 1 I membered cycle. This structural evolution is essentially the result of the reorientation of the hydrophobic side chains that are probably directly involved in peptide-antibody recognition.