Ligand Docking to MHC Class I Molecules

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1 Ligand Docking to MHC Class I Molecules
Lam Tze Hau

2 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

3 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.

4 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.

5 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 silico approaches: Sequence-based Structure-based

6 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.

7 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

8 Molecular Docking - AutoDock
Garrett M. Morris et al , 2010 AutoDock uses semi empirical free energy force field to evaluate conformations during docking simulation. Allows configurations for flexible ligand and receptor side chains.

9 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.


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