A combined NMR and molecular dynamics simulation study to determine the conformational properties of agonists and antagonists against experimental autoimmune encephalomyelitis

Bioorg Med Chem. 2008 Mar 1;16(5):2171-82. doi: 10.1016/j.bmc.2007.11.083. Epub 2008 Jan 1.

Abstract

Myelin basic protein (MBP) is one of the best characterized autoantigens causing multiple sclerosis (MS), via a procedure that involves a stable formation of the trimolecular complex of a T-cell Receptor (TCR), an MBP epitope, and the receptor HLA-DR2b. Experimental autoimmune encephalomyelitis (EAE) is considered as an instructive model for MS in humans, and plenty of X-ray data is available for a number of EAE inducing peptide-receptor complexes. To date, though, there are no data available for complexes involving peptides reversing EAE, namely antagonists. Conformational properties of the EAE inducing epitope MBP(87-99) were analyzed in DMSO using the NOE connectivities and vicinal H(N)-H(alpha) coupling constants, and compared with the antagonist altered peptide ligands. A robust method, which is based on a combination of molecular dynamics and energy minimization, is proposed for identifying the putative bioactive conformations. Generated conformations are compared with the known X-ray structure of MBP(83-96) (human sequence numbering) in the HLA-DR2b complex. The structural motif for the agonist-antagonist activity is discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaline Phosphatase / antagonists & inhibitors*
  • Alkaline Phosphatase / metabolism
  • Amides / chemistry
  • Amino Acid Sequence
  • Animals
  • Computer Simulation
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Encephalomyelitis, Autoimmune, Experimental / enzymology
  • Hydrogen Bonding
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Conformation
  • Molecular Sequence Data
  • Myelin Basic Protein / agonists*
  • Myelin Basic Protein / antagonists & inhibitors*
  • Myelin Basic Protein / chemistry
  • Myelin Basic Protein / metabolism
  • Protons
  • Temperature

Substances

  • Amides
  • Myelin Basic Protein
  • Protons
  • Alkaline Phosphatase