Molecular dynamics study of a complex between the human histocompatibility antigen HLA‐A2 and the IMP58‐66 nonapeptide from influenza virus matrix protein

Abstract

The structure of the influenza‐virus‐matrix‐protein (IMP) 58‐66 nonapeptide, bound to the major‐histocompatibility‐complex‐encoded human leukocyte antigen (HLA) A2 protein was studied by molecular dynamics simulation. Starting from the extra electron density map of peptides co‐crystallized with HLA‐A2, the nonapeptide IMP58‐66 was docked residue by residue in the protein binding cleft. The complex was simulated for 100 ps in a shell of 1372 water molecules. The averaged simulated HLA‐A2 conformation was found to be similar to the crystal structure (0.182 nm RMS deviation, for the backbone atoms of the α1‐α2 domain). Nine out of the 14 hydrogen bonds observed in the antigen‐binding site were reproduced in the simulation. The IMP58‐66 peptide exhibits an extended conformation with kinks at positions 3 and 5. The side chains of residues 2, 3 and 9 develop van der Waals' interactions with hydrophobic pockets of HLA‐A2, corresponding to polymorphic residues of the major‐histocompatibility‐complex‐encoded proteins. Both the N‐terminus and C‐terminus of the nonapeptide were anchored in the antigen‐binding groove by hydrogen bonds with conserved amino acids. The N‐terminus was more flexible and contacts four HLA‐A2 conserved tyrosines (Tyr7, Tyr59, Tyr159 and Tyr171) and Glu63 by direct or water‐relayed hydrogen bonds. Water intercalation occurred only around the N‐terminus of the peptide, the C‐terminal carboxylate forming strong hydrogen bonds with polar residues (Tyr84 and Thr143) and a salt bridge with Lys146 all over the molecular dynamics simulation. This model is fully compatible with the recently published crystal structure of the HLA‐B27 protein, complexed by a mixture of self nonapeptides [15] Copyright © 1992, Wiley Blackwell. All rights reserved