Flexibility of the MHC class II peptide binding cleft in the bound, partially filled, and empty states: A molecular dynamics simulation study

Rakina Yaneva, Sebastian Springer, Martin Zacharias

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Major histocompatibility (MHC) Class II cell surface proteins present antigenic peptides to the immune system. Class II structures in complex with peptides but not in the absence of peptide are known. Comparative molecular dynamics (MD) simulations of a Class II protein (HLA-DR3) with and without CLIP (invariant chain-associated protein) peptide were performed starting from the CLIP-bound crystal structure. Depending on the protonation of acidic residues in the P6 peptide-binding pocket the simulations stayed overall dose to the start structure. The simulations without CLIP showed larger conformational fluctuations especially of α-helices flanking the binding cleft. Largest fluctuations without CLIP were observed in a helical segment near the peptide C-terminus binding region matching a segment recognized by antibodies specific for empty Class II proteins. Simulations on a Val86Tyr mutation that fills the peptide N-terminus binding P1 pocket or of a complex with a CLIP fragment (dipeptide) bound to P1 showed an unexpected long range effect. In both simulations the mobility not only of P1 but also of the entire binding cleft was reduced compared to simulations without CLIP. It correlates with the experimental finding that the CLIP fragment binding to P1 is sufficient to prevent antibody recognition specific for the empty form at a site distant from P1. The results suggest a mechanism how a local binding event of small peptides or of an exchange factor near P1 may promote peptide binding and exchange through a long range stabilization of the whole binding cleft in a receptive (near bound) conformation.

Original languageEnglish
Pages (from-to)14-27
Number of pages14
JournalBiopolymers
Volume91
Issue number1
DOIs
StatePublished - 2009
Externally publishedYes

Keywords

  • Class II
  • Empty class II structure
  • MHC class II flexibility
  • Molecular simulation
  • Peptide loading
  • Protein dynamics
  • Tapasin dass II interaction

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