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Database usage details:

Search by categories:

This search function allows you to access MPID-T2 by MHC class, MHC allele, organism, peptide length, dataset of your interest and TR type. To get the results of pMHC complexes from class I and/or class II structures, choose the MHC Class (i.e. MHC class I, MHC class II or ALL) in the option, select "ALL" in the MHC Allele option, select "ALL" in the Organism option, select "ALL" in the Peptide Length option, check/uncheck the Non redundant checkbox for the data set you are interested (i.e. redundant or non-redundant) and select "NONE" in the TR Type option.

You can also limit the output parameters by customizing or selecting the output parameters of your interest from the output parameters menu.

Note: (i) The structure 2ICW (PDB code) is listed as a TR/pMHC structure in this database, however, the values for its TR/pMHC interaction parameters are either not listed or are listed as "0" within the entry since it has a super-antigen between the TR and the pMHC which prevents actual TR/pMHC interaction by mediating the TR/pMHC binding. Similarly, its TR/pMHC ligplot images show the pMHC ligplots as it is not possible to compute the TR/pMHC ligplot image due to the presence of the superantigen.

(ii) Within the "ALIGNMENT" page of MPID-T2, under the "pMHC conserved residues by MHC allele & peptide length" section, only the structural aligments for two or more pMHC complexes having the same allele and peptide length, are provided.

Search by PDB Data:

This search function allows you to access MPID-T2 by PDB-ID, resolution, release year and combined querying based on resolution and release year.

To query by PDB-ID, enter the valid four letter PDB code (e.g. 1hhj) and click the search button. To enter multiple PDB codes, use "," as delimiter as shown in the text area (e.g. 1hhh,1hhj).

To query by resolution, enter the resolution with two decimals (e.g. 3.20,3.00) and click the search button. To enter multiple resolutions, use "," as delimiter (e.g. 3.00,3.20).

To query by PDB release year, enter the release year (e.g. 2001) and click the search button. To enter multiple PDB release years use "," as delimiter (e.g. 2001,2000).

To do a combined query on resolution and release year, choose the "AND" option for combined querying and "OR" option to query either by resolution or release year. Click the search button.

Definition of Interaction Parameters:

Predifined Interaction Parameters: (Tong et al., 2006)

Total Hydrogen Bonds - This could refer to either total pMHC hydrogen bonds or total TR/pMHC hydrogen bonds. Total pMHC hydrogen bonds represent the total number of hydrogen bonds between the class I MHC (α-Chain) and the peptide or class II MHC (α and β-Chains) and the peptide that was calculated using the program HBPLUS (McDonald and Thornton, 1994). Total TR/pMHC hydrogen bonds represent the total number of hydrogen bonds between the pMHC and the TR that was again calculated using the program HBPLUS (McDonald and Thornton, 1994).

Interface Area - Interface area is calculated using the program NACCESS (Hubbard and Thornton, 1993) with angstrom square as the unit of measurement. Interface area for class I pMHC complexes is defined as the change in solvent accessible surface area (delta ASA) when going from a monomeric MHC protein to a dimeric pMHC complex state, while the interface area for class II pMHC complexes is defined as the change in their solvent accessible surface area when going from a dimeric MHC protein to a trimeric pMHC complex state. Similarly, TR/pMHC interface area is defined as the change in solvent accessible surface area (delta ASA) when going from a dimeric pMHC ligand to a tetrameric TR/pMHC complex state for class I TR/pMHC complexes and when going from a trimeric pMHC ligand to a pentameric TR/pMHC complex state for class II TR/pMHC complexes.

Gap Volume - Gap volume gives a measure of the complementarity of the interacting surfaces. The volume of the gaps between the two interacting subunits is calculated using the program SURFNET (Laskowski, 1991). Each pair of subunit atoms are considered in turn, placing a sphere (maximum radius 5.0 angstroms) halfway between the surfaces of the two atoms, such that its surface touches the surfaces of the atoms in the pair. Checks are made to test is any other atoms intercepts this sphere and each time an intercept is detected the size of the sphere is reduced accordingly. Is at any time the size of the sphere falls below a minimum (minimum radius 1.0 angstroms) the sphere is discarded. If the sphere remains after all checks its size is recorded. The sizes of all the allowable gap-spheres are then used to calculate the gap volume between the two subunits. The volume covered by the gaps between the peptide and the MHC binding groove residues upon pMHC complex formation is called the pMHC gap volume and is measured in terms of angstrom cube. Similarly, the volume covered by the gaps between the pMHC and the TR interfaces upon TR/pMHC complex formation is called the TR/pMHC gap volume.

Gap Index - One essential feature in receptor-ligand binding is the electrostatic and geometric complementarity observed between associating molecules. Gap index is used as a means to evaluate the complementarity of interacting surfaces. The gap index is calculated using the formula:

Gap Index=Gap Volume/Change in solvent accessible surface area (delta ASA).

The unit for gap index is angstrom. The gap index between the peptide and the MHC protein is thus calculated using the formula

pMHC Gap Index = pMHC Gap Volume / pMHC delta ASA.

Similar to pMHC gap index, the gap index between the pMHC and the TR is calculated using the formula

TR/pMHC Gap Index = TR/pMHC Gap Volume / TR/pMHC delta ASA.

New Interaction Parameters: (Khan and Ranganathan, unpublished results)

Binding Energy (BE) - The interaction of most ligands with their binding sites can be characterized in terms of a binding free energy or binding energy. In general, high binding energy results from greater intermolecular force between the two molecules in question, while low energy ligand binding involves less intermolecular force between the two molecules. In the context of TR/pMHC binding, high energy binding involves a longer residence time for the TR on its respective pMHC. High energy binding of the pMHC to TR is often physiologically important as some of the binding energy can be used to cause a conformational change in the TR, resulting in a physiological response or T cell response. In literature, the experimental binding affinity is usually derived from the binding constant of the interaction such as kon, koff, Kd and Ka. The thermodynamic formulae used are as follows:

DG = -RT ln Ka

Ka = 1/Kd = kon/koff

Where Kd is the dissociation constant, R is the universal gas constant, T is the absolute temperature and Ka is the association constant. The program DCOMPLEX (Liu et al., 2004) is used to calculate the binding energies between the peptide and MHC for all the structures and between pMHC and TR for all TR/pMHC structures with Kcal/mol as the unit. The algorithm of this program uses the same thermodynamic formulae described above to compute the binding energy. Since binding energy is also referred to as binding free energy, the most negative value is considered the best.

Molecular Surface Electrostatic Potential (MSEP) - MSEP in proteins is a result of charged side chains of the amino acid residues and bound ions. These potentials play a vital role in protein folding, stability, enzyme catalysis and specific protein-protein recognitions. MSEP similarity between any two protein molecules is a measure of the similarity in their composition of charged residues. Interactions between the TR and pMHC in all the structures depend vastly on the charges that the binding site on the pMHC molecule displays. Thus, the web server webPIPSA (Richter et al., 2008) was used to calculate the MSEP of only the pMHC and TR binding interfaces in all the structures and TR/pMHC structures, respectively. Structural models of only the pMHC and TR interacting parts were used for this analysis. ICM (Abagyan et al., 1994) was later used to visualize and make the electrostatic images (an example is shown below in Supplementary Figure 1a, b) of all the structures for visual analysis.

TR docking angle - TR docking angle is defined as the angle formed by the TR paratope (footprint) on the pMHC interface with respect to the linear axis of the cognate peptide within the MHC groove. After MSEP calculations, the respective pMHC and TR interfaces were matched for complementarities of charges and the corresponding charges were numbered accordingly on both the interfaces. These charged residues were cross verified with the list of pMHC and TR interacting residues collated. The charged residues missing from these lists were omitted and the charges were renumbered for consistency in results. A line was drawn which connects the numbers on each of the pMHC using ICM (Abagyan et al., 1994). Once connected, the numbers on a given pMHC interface formed an ellipsoidal shape, which determines the TR paratope on the pMHC. These ellipses were noticed to be at a certain angle with respect to the C-alpha backbone axes of the respective cognate peptides across the entire TR/pMHC dataset. Finally, straight lines were drawn diagonally across the ellipses which cut the axes of the bound peptides at a given angle. These angles were measured using ICM (Abagyan et al., 1994) and are called TR docking angle on the pMHC interfaces.

Contact Area (CA) - Change in solvent accesible surface area and contact area are similar, yet there is a significant difference between them because change in accesible surface area is a measure of the interaction area at a molecular level but contact area between any two protein molecules is defined as the area enclosed by the interacting residues of the two molecules. Values for contact area between the peptide and MHC for all the structures and between pMHC and TR for all TR/pMHC structures were computed using the ICM program (Abagyan et al., 1994) with angstrom square as the unit of measurement. The algorithm creates a surface around a residue "i" from the first molecule, which interacts with the residue "j" from the second, by rolling a probe of radius "R" over the van der Waals surface of the residue atoms and tracing the centre of the probe. It then finds the part of this surface that is occluded by van der Waals surfaces of atoms of residue "j". The resulting area is called the contact area between "i" and "j" (an example is shown below in Supplementary Figure 1c).

Supplementary Figures:

Figure S1 - Examples of Molecular Suface Electrostatic Potential (MSEP) and Contact Area (CA) as TR/pMHC interaction parameters. a. MSEP for a Tax-HLA-A2 pMHC interface (PDB code: 1AO7). b. MSEP for A6 TR interface (1AO7). c. CA between two interacting residues T73 and I53 from the alpha-1 (G-ALPHA1) helix of a MHC-I (HLA-A2) allele and the beta-chain of a Vbeta17Valpha10.2 TR, respectively, in the TR/pMHC complex 1OGA (PDB code). The component parts/domains of both pMHC and TR interfaces are labeled in a. and b. TR interface in b. has been rotated 180 degrees with respect to the pMHC interface in a. Valpha domain of TR interface interacts with alpha2 (G-ALPHA2) helix of the MHC and N-terminal half of the peptide, whereas, Vbeta domain interacts with alpha1 (G-ALPHA1) helix of the MHC and C-terminal half of the peptide. The ellipse (in yellow, with major axis marked diagonally) represents the paratope of the TR on the pMHC surface, while the green line represents the peptide axis. The TR docking angle, theta, is the angle between the peptide axis and the major axis of the ellipse.

Figure S2 - Screenshots of the search page and the search result for a TR/pMHC-I structure (1AO7) from the MPID-T2 database. a. The web interface for searching with user defined input parameters (including TR type). b. Search result for 1AO7 depicting various fields of pMHC and TR/pMHC information. Values for new pMHC and/or TR/pMHC interaction parameters: BA, CA and TR docking angle can be noted while MSEP images for both pMHC and TR interfaces can be accessed by clicking on the "View Electrostatic Potential" links provided as shown in the callout boxes. Structural alignment for TR/pMHC complexes based on TR types can also be visualized.

Useful resources:

Some useful links to pMHC and TR/pMHC databases and epitope prediction tools are provided below.

  • IMGT - The International ImMunoGeneTics information system
  • IMGT/3Dstructure-DB: A database for immunoglobulin, T cell receptor and MHC structural data.
  • IMGT/HLA Database
  • SYFPEITHI: A database of MHC ligands and peptide motifs (Ver. 1.0)
  • NCBI dbMHC
  • MHCBN: Comprehensive Database of MHC Binding and Non-Binding Peptides
  • HLA Informatics Group, ANRI
  • EPIMHC: A curated database of MHC ligands
  • CID - Cancer Immunome Database
  • Epitome - Database of structurally inferred antigenic epitopes in proteins
  • HLA Database Search
  • AntiJen
  • EpiJen
  • VaxiJen
  • SMM - Prediction of high affinity HLA-A2 binding peptides
  • NetMHC
  • SVMHC - a prediction tool for MHC class I and MHC class II binding peptides
  • PAProC (Prediction Algorithm for Proteasomal Cleavages)
  • PREDEP - MHC Class I epitope prediction
  • MHCPred
  • MAPPP - MHC-I antigenic peptide processing prediction
  • ePitope Informatics - Epitope prediction and protein analysis
  • NetChop
  • Histo
  • EPIPREDICT
  • NCBI
  • BIMAS - HLA Peptide Binding Predictions
  • ASHI - American Society for Histocompatibility and Immunogenetics
  • HIV Molecular Immunology Database
  • EpiVax
  • OMIM
  • Medline
  • IEDB - Immune Epitope Database
  • MHC-Thread: HLA class II predictions
  • RANKPEP: Prediction of binding peptides to Class I & II MHC molecules
  • ProPred-I: The Promiscuous MHC Class-I Binding Peptide Prediction Server
  • ProPred: MHC class II binding peptide prediction server
  • MHCBench - Evaluation of MHC binding peptide prediction algorithms