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Ligand Docking to MHC Class I Molecules . Lam Tze Hau. Major Histocompatibility Complex (MHC) Class I. Play a vital role in the adaptive immune response. Generate maximal immunological protection against a large repertoire of pathogens.

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major histocompatibility complex mhc class i
Major Histocompatibility Complex (MHC) Class I
  • Play a vital role in the adaptive immune response.
  • Generate maximal immunological protection against a large repertoire of pathogens.
  • MHC bind to peptides of diverse sequences degraded from pathogen proteins and present on cells surface for T-cell recognition to initial and regulates immune responses

Tobias Jung et al, 2009

major histocompatibility complex mhc class i1
Major Histocompatibility Complex (MHC) Class I
  • MHC class I molecules are highly polymorphic.
  • 3 major human MHC genes commonly referred as HLA (A, B, C).
  • More than 1000 of HLA class I alleles are known.
  • Strong bias for stable binding of short peptides in the range of 8 – 10 residues.
  • Peptide binding specificity to MHC is allele specific.
structure of class i mhc peptide complex
Structure of class I MHC-peptide complex
  • Binding clefts contain polymorphic ‘pockets’ that fits the complementary residues of the binding peptides.
  • H-bonds between the peptide termini and the conserved MHC residues anchor the N- and C- termini.
  • Backbone conformation of the 3 N-terminal peptide residues and the 2 C-terminal residues is similar in many different MHC-pepitdes structures.
  • These positions contribute most of the binding interactions.
  • Specific MHC alleles bind peptides with similar anchor residues.
mhc class i peptides prediction
MHC class I peptides prediction
  • The understanding of the peptide selection and interactions for different MHC alleles is important.
  • It is crucial step for establishing T-cell-based immunotherapy for infectious diseases , autoimmune diseases and cancer.
  • Experimental studies are time-consuming and expensive.
  • In silicoapproaches:
    • Sequence-based
    • Structure-based
structure based approach molecular docking
Structure based approach-Molecular Docking
  • Useful technique to study intermolecular interactions or structure based drug design.
  • Motivation of docking simulation
    • To determine the most probable translational, rotational and conformational position of a given ligand-receptor.
    • To evaluate the relative goodness-of-fit for different computed complexes.
  • Docking simulation is highly combinatorial in nature.
  • Search on the conformation space increases exponentially with increase molecule size and sampling space.
molecular docking autodock
Molecular Docking - AutoDock
  • AutoDock is a suite of automated docking tools.
  • Consist of 2 main programs:
    • AutoGrid pre-calculates these grids.
    • AutoDock performs the docking of the ligand to a set of grids describing the target protein
molecular docking autodock1
Molecular Docking - AutoDock
  • AutoDock uses semi empirical free energy force field to evaluate conformations during docking simulation.
  • Allows configurations for flexible ligand and receptor side chains.

Garrett M. Morris et al , 2010

molecular docking autodock2
Molecular Docking - AutoDock
  • AutoDock molecular simulation of a peptide (9mer) onto MHC binding cleft requires approx ~ 4 to 6 hours. (50 conformations run with using Lamarckian genetic algorithm as the search method).
  • Docking thousands of potential pathogen peptides against hundreds of MHC class I molecules requires enormous amount of computational power.