IEDB Analysis Resource

Computational Methods for Mapping Mimotopes to Protein Antigens

Mimotopes are molecules - often peptides - that are recognized by antibodies or T cells that were primed to recognize a different epitope. For antibody epitope mapping, peptide mimotopes can be selected from a combinatorial library (usually peptides from a specific protein antigen) on binding to a specific monoclonal antibody with high affinity; they are commonly obtained using page display. Experimental data on mimotopes can be found in the IEDB, MimoDB (http://immunet.cn/mimodb/index.html) and journal publications. Mimotopes can mimic essential features of genuine epitopes and therefore their mapping to the antigen is a logical and essential step of the mimotope analysis. This page provides information on available methods for mimotope mapping, how to search the IEDB for mimotopes, and an example of a mimotope dataset and the results of its mapping, using the available web servers hosted outside the IEDB.

Methods available as web servers and operational as of July 2014 (they all require the user submitting an antigen protein 3D structure, providing either PDB ID of the structure or the pdb file)
Other published methods (unavailable as web servers)
If an antigen sequence is not available
Publications on mimotope mapping tools evaluation
How to search for mimotopes in the IEDB (note that IEDB does not contain HIV-related data) As of July 28, 2014, this search returned 5,995 assays curated from 334 references
Example of the mimotope mapping to the protein with known structure
For PMID: 23006741, the IEDB provides 16 mimotopes recognized by a monoclonal antibody directed against the vaccinia virus A33 protein, MAb-1G10. The mimotope mapping and subsequent experimental analysis presented in this paper showed that D115 and L118 were essential epitope residues. Inspection of the GenBank record for VACV A33, or the EEV membrane phosphoglycoprotein, http://www.ncbi.nlm.nih.gov/protein/38349023, reveals that the 3D structure of this protein is available and has PDB ID 3K7B, in which chains A and B represent a protein dimer.

Here is the list of 16 mimotopes as provided in IEDB:
ACCDDWPHEC ACGDDWPHECGGGSAK ACKPTWPFEC ACNLYNEPFC ACNLYNEPLC ACQLKWPFEC ACQTSYPYEC ACSNSWPHEC ACTSYNEPLC ACTSYNEPLCGGGSAK ACTVFNEPFC ACWYDSLIFC MKPALCEPLCG NPYCEPVCQDWA QLTAQHRDSLSS SLMRELCEPRCE

Below are the results of the mapping of the above provided mimotopes using the MIMOX, Pepitope (three methods) and EpiSearch servers. The task of mapping these particular mimotopes is challenging as peptides were obtained from a combinatorial library and had no matches in the VACV A33 protein. Five epitope residues predicted by all methods are in bold; they however do not include residues D115 and L118, which are functionally essential epitope residues.
MIMOX
We used http://immunet.cn/mimox/cgi-bin/mimox2.pl, submitting to its form the peptide sequences (above) and specifying PDB ID 3K7B and chain A.

Results:
Best cluster (37 out of 88 protein residues), Center Residue P134, Score 0.98:
L103, Y105, Q106, S108, C109, Y110, I111, L112, H113, A123, S131, T132, L133, P134, N135, K136, S137, D138, V139, T142, I145, Y147, E149, D150, T151, S154, D155, G156, N157, P158, R176, K177, Y178, F179, C180, V181, K182

The inspection of the 3D image of the structure with the mapped predicted epitope showed that the epitopes is too large and lies at both the protein surface and interior and on opposite sides of the protein.
Pepitope server at http://pepitope.tau.ac.il/
As above, we used PDB ID 3K7B and chain A. The server requires submitting peptides in the fasta-format and doesn't accept sequences longer than 14 aa, therefore the following 14 peptides were submitted:
> ACCDDWPHEC > ACKPTWPFEC > ACNLYNEPFC > ACNLYNEPLC > ACQLKWPFEC > ACQTSYPYEC > ACSNSWPHEC > ACTSYNEPLC > ACTVFNEPFC > ACWYDSLIFC > MKPALCEPLCG > NPYCEPVCQDWA > QLTAQHRDSLSS > SLMRELCEPRCE

Results

PepSurf:
Best cluster (21 out of 88 protein residues), Score 28.016: CYS100, ASN101, GLY102, LEU103, SER108, CYS109, ILE111, LEU112, HIS113, SER114, ASP115, TYR116, THR127, ALA128, GLU129, SER130, SER131, THR132, LYS177, VAL181, LYS182

MAPITOPE:
Best cluster (10 out of 88 protein residues): GLU98, SER99, CYS100, ASN101, GLY102, LEU103, TYR104, TYR105, GLN106, GLY107, SER108, CYS109, ILE111, VAL181

Combined:
(8 out of 88 protein residues, intersects cluster number 1 of PepSurf with cluster number 1 of Mapitope): CYS100, ASN101, GLY102, LEU103, SER108, CYS109, ILE111, VAL181

The predicted epitope is compact and located on the protein surface.
EpiSearch (http://curie.utmb.edu/episearch.html)
The server doesn't allow to provide PDB ID, the user therefore needs to download pdb text file from http://www.pdb.org/pdb/explore/explore.do?structureId=3k7b and modify it in any text editor by removing all lines starting with ATOM and containing chain B, leaving only chain A.

Results:
Best cluster (24 out of 88 protein residues), Center Residue V181, Score 14.22: C100, G102, L103, Y104, Y105, Q106, G107, S108, C109, I111, L112, H113, A123, T127, E129, S130, S131, T132, N135, D138, S154, V181, K182, T183


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