Gene
Ther Mol Biol Vol 12, 147-166, 2008
Prediction
of antigenic binders from c-terminal domain Human
papillomavirus oncoprotein e7
Research
Article
Virendra S Gomase1,2*,
Somnath Tagore1, Krishnan Shyamkumar1
1Department of Bioinformatics, Padmashree Dr. D.Y.
Patil University,
CBD Belapur, Navi Mumbai, 400614, India
2Department of Computer Science and Information
Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, 431004
(MS), India
__________________________________________________________________________________
*Correspondence: Virendra
S. Gomase, Department of Bioinformatics,
Padmashree Dr. D.Y. Patil University, Plot No-50, Sector-15, CBD Belapur, Navi
Mumbai, 400614, India; Tel- +91-22-27563600; Fax- +91-39286176; Mobile-
+91-9226960668; Mail- virusgene1@yahoo.co.in
Key words: oncoprotein e7, TAP transporter,
MHC, APCs, TCR
Abbreviations: antigen presenting cells,
(APCs); Human papillomavirus, (HPV); Position
Specific Scoring Matrices, (PSSMs); sexually transmitted
disease, (STD); support vector machine, (SVM); T
cell receptors, (TCR); T cell receptors, (TCR)
Received: 30 May
2008 Revised: 24 June 2008
Accepted: 25 June
2008; electronically published: August 2008
Summary
Human
papillomavirus (HPV) is one of the most common causes of sexually transmitted
disease (STD). Human papillomavirus viral peptides are most suitable for
subunit vaccine development because with single epitope, the immune response
can be generated in large population. TAP is a transporter associated with MHC class
I restricted antigen processing. The TAP is heterodimeric transporter belong to
the family of ABC transporter, that uses the energy provided by ATP to
translocate the peptides across the membrane. The subset of this transported
peptide will bind MHC class II molecules and stabilize them. These MHC-peptide
complexes will be translocated on the surface of antigen presenting cells
(APCs). In this assay we predicted the binding affinity of Human papillomavirus
oncoprotein e7 having 56 amino acids, which shows 49 nonamers. Small peptide
regions found as 9-RHKILCVCC (score 6.186), 34-LRTLQQLFL (Score- 6.091),
31-AEDLRTLQQ (Score- 5.979), 8-QRHKILCVC (Score- 5.960), 45-LSFVCPWCA
(Score-5.604), known as oncoprotein e7 TAP transporter. Adducts of MHC and
peptide complexes are the ligands for T cell receptors (TCR). These complexes
elicit the immune response for clearing various intracellular infections.
Prediction methods based on the specificity of TAP transporter will complement
the wet lab experiments and speed up the knowledge discoveries on the basis of
these two computational algorithms.
I. Introduction
A. Human papillomavirus
Papillomaviruses are highly species specific and do
not infect other species, even under laboratory conditions. Humans are the only
known reservoir for HPV. Papillomaviruses are nonenveloped viruses of
icosahedral symmetry with 72 capsomeres that surround a genome containing
double-stranded circular DNA with approximately 8000 base pairs.
Papillomaviruses are thought to have 2 modes of replication. One is stable
replication of the episomal genome in basal cells; the other is runaway, or
vegetative, replication in more differentiated cells to generate progeny virus.
Although all cells of a lesion contain the viral genome, the expression of
viral genes is tightly linked to the state of cellular differentiation. Most
viral genes are not activated until the infected keratinocyte leaves the basal
layer. Production of virus particles can occur only in highly differentiated
keratinocytes; therefore, virus production only occurs at the epithelial
surface where the cells are ultimately sloughed into the environment (Alani et al, 1998).
B. Molecular aspects
The E7 oncoprotein from human Papillomavirus (HPV) mediates cell transformation in
part by binding to the human pRb tumor suppressor protein and E2F
transcription factors, resulting in the dissociation of pRb from E2F
transcription factors and the premature cell progression into the
S-phase of the cell cycle. This activity is mediated by the LXCXE motif and the CR3 zinc binding domain of the E7
protein (Liu et al, 2006).
C. MHC Class-I binding peptides
The
new paradigm in vaccine design is emerging, following essential discoveries in
immunology and development of new MHC Class-I binding peptides prediction
tools. MHC molecules are cell surface glycoproteins, which take active part in
host immune reactions. The involvement of MHC class-I in response to almost all
antigens and the variable length of interacting peptides make the study of MHC
Class I molecules very interesting. MHC molecules have been well characterized
in terms of their role in immune reactions (Singh et al, 2002; Bhasin et al, 2003; Cui et al, 2006).
They bind to some of the peptide fragments generated after proteolytic cleavage
of antigen (Kumar et al, 2007).
This binding acts like red flags for antigen specific and to generate immune
response against the parent antigen. So a small fragment of antigen can induce
immune response against whole antigen. Human papillomavirus viral peptides are
most suitable for subunit vaccine development because with single epitope, the
immune response can be generated in large population.TAP is a transporter
associated with MHC class I restricted antigen processing. The TAP is
heterodimeric transporter belong to the family of ABC transporter, that uses
the energy provided by ATP to translocate the peptides across the membrane (Bhasin et al,
2004). The subset of this transported peptide will bind MHC class I
molecules and stabilize them. These MHC-peptide complexes will be translocated
on the surface of antigen presenting cells (APCs). This theme is implemented in
designing subunit and synthetic peptide vaccines (Gomase et al, 2007).
II. Materials and
Methods
A. Protein Sequence analysis
We
analysed the oncoprotein sequence of Human papillomavirus oncoprotein e7 (Ohlenschlager et al, 2006).
B.
Prediction of antigenicity
This
program predicts those segments from within viral oncoprotein that are likely
to be antigenic by eliciting an antibody response (Nakagawa et al, 2004).
Antigenic epitopes is determined using Gomase method in 2007, B-EpiPred Server,
Hopp and Woods, Welling, Parker, Kolaskar and Tongaonkar antigenicity methods (Gomase 2006; Larsen et al,
2006; Hopp et al, 1981; Welling
et al, 1985; Parker et al, 1986; Kolaskar et al, 1990).
Predictions are based on a table that reflects the occurrence of amino acid
residues in experimentally known segmental epitopes.
C.
Prediction of protein secondary structure
The
important concepts in secondary structure prediction are identified as: residue
conformational propensities, sequence edge effects, moments of hydrophobicity,
position of insertions and Deletions in aligned homologous sequence, moments of
conservation, auto-correlation, residue ratios, secondary structure feedback
effects, and filtering (Robson et al, 1993).
D.
Finding the location in solvent accessible regions
For
setting the solvent accessible regions in protein, type of plot determine the
hydrophobic scale and it is utilized for prediction. This may be useful in
predicting membrane-spanning domains, potential antigenic sites and regions
that are likely exposed on the protein surface (Aboderin 1971; Bull et al, 1974; Chothia 1976; Manavalan et
al, 1978; Janin 1979; Wilson et al, 1981; Wolfenden et al, 1981; Kyte et al,
1982; Fauchere et al, 1983; Sweet et al, 1983; Eisenberg et al, 1984a,b; Guy
1985; Miyazawa et al, 1985; Rose et al, 1985; Rao 1986; Abraham et al, 1987;
Roseman 1988; Cowan et al, 1990; Black et al, 1991; Wilkins et al, 1999).
E.
Prediction of MHC Binding peptide
MHC2Pred predicts peptide binders to MHCI and
MHCII molecules from protein sequences or sequence alignments using Position
Specific Scoring Matrices (PSSMs). In addition, we predicts those MHCI ligands
whose C-terminal end is likely to be the result of proteosomal cleavage (Brusic et al, 1998; Bhasin et al, 2005;
Gomase et al, 2008).
III. Result and interpretation
A. The oncoprotein sequence is 56 residues
long as-
GSHMAEPQRHKILCVCCKCDGRIELTVESSAEDLRTLQQLFLSTLSFVCPWCATNQ.
B. Prediction of Antigenic peptides
In these methods we found the antigenic determinants
by finding the area of greatest local hydrophilicity. The Hopp-Woods scale was
designed to predict the locations of antigenic determinants in a protein,
assuming that the antigenic determinants would be exposed on the surface of the
protein and thus would be located in hydrophilic regions (Figure 1). Its values are derived from the transfer-free energies
for amino acid side chains between ethanol and water. Welling antigenicity plot
gives value as the log of the quotient between percentage in a sample of known
antigenic regions and percentage in average proteins (Figure 2). We also study B-EpiPred Server, Parker, Kolaskar and Tongaonkar
antigenicity methods and the predicted antigenic fragments can bind to
MHC molecule is the first bottlenecks in vaccine design (Figures 3-5).
C. Secondary alignment
The Robson and Garnier
method predicted the secondary structure of pathogenicity protein. Each residue
is assigned values for alpha helix, beta sheet, turns and coils using a window
of 7 residues (Figure 6). Using these information parameters, the
likelihood of a given residue assuming each of the four possible conformations
alpha, beta, reverse turn, or coils calculated, and the conformation with the
largest likelihood is assigned to the residue.
D. Solvent accessible regions
Solvent accessible scales for delineating hydrophobic
and hydrophilic characteristics of amino acids and scales are developed for
predicting potential antigenic sites of globular proteins, which are likely to
be rich in charged and polar residues. It was shown that a oncoprotein
is hydrophobic in nature and contains segments of low complexity and
high-predicted flexibility (Figures
7-26).
Figure 1. Hopp & Woods hydrophobicity plot of oncoprotein e7.
Figure 2. Welling hydrophobicity plot of oncoprotein e7.
Figure 3. B.cell epitopes are the
sites of molecules that are recognized by antibodies of the immune system for
the oncoprotein e7.
Figure 4. Parker HPLC hydrophobicity plot of oncoprotein e7.
Figure 5. Kolaskar and Tongaonkar
antigenicity are the sites of molecules that are recognized by antibodies of
the immune system for the oncoprotein e7.
Figure
6. Secondary structure plot of pathogenicity protein.
Figure 7. Sweet hydrophobicity plot of oncoprotein e7.
Figure 8. Kyte & Doolittle hydrophobicity plot of oncoprotein e7.
Figure 9. Abraham & Leo hydrophobicity plot of oncoprotein e7.
Figure 10. Bull & Breese hydrophobicity plot of oncoprotein e7.
Figure 11. Guy hydrophobicity plot of oncoprotein e7.
Figure 12.Miyazawa hydrophobicity plot of oncoprotein e7.
Figure 13. Roseman hydrophobicity plot
of oncoprotein e7.
Figure 14. Cowan HPLC pH7.5 hydrophobicity plot of oncoprotein e7.
Figure 15. Rose hydrophobicity plot of oncoprotein e7.
Figure 16. Eisenberg hydrophobicity plot of oncoprotein e7.
Figure 17. Manavalan hydrophobicity plot of oncoprotein e7.
Figure 18. Black hydrophobicity plot of oncoprotein e7.
Figure 19. Fauchere hydrophobicity plot of oncoprotein e7.
Figure 20. Janin hydrophobicity plot of oncoprotein e7.
Figure 21. Rao & Argos hydrophobicity plot of oncoprotein e7.
Figure 22. Wolfenden hydrophobicity plot of oncoprotein e7.
Figure 23. Wilson HPLC hydrophobicity plot of oncoprotein e7.
Figure 24. Cowan HPLC pH3.4 hydrophobicity plot of oncoprotein e7.
Figure 25.Rf mobility hydrophobicity plot of oncoprotein e7.
Figure 26. Chothia hydrophobicity plot of oncoprotein e7.
E. Prediction of MHC Binding peptides
These MHC binding peptides are sufficient for
eliciting the desired immune response. The prediction is based on cascade
support vector machine, using sequence and properties of the amino acids. The
correlation coefficient of 0.88 was obtained by using jack-knife validation
test. In this test, we found the MHCI and MHCII binding regions (Tables 1, 2). MHC molecules are cell
surface glycoproteins, which take active part in host immune reactions and
involvement of MHC class-I and MHC II in response to almost all antigens. In
this assay we predicted the binding affinity of oncoprotein having 56 amino
acids, which shows different nonamers (Tables
1, 2). For development of MHC binder prediction method, an elegant machine
learning technique support vector machine (SVM) has been used. SVM has been
trained on the binary input of single amino acid sequence. In this assay we
predicted the binding affinity of Human papillomavirus oncoprotein e7 having 56
amino acids, which shows 49 nonamers. Small peptide regions found as
9-RHKILCVCC (score 6.186), 34-LRTLQQLFL (Score- 6.091), 31-AEDLRTLQQ (Score-
5.979), 8-QRHKILCVC (Score- 5.960), 45-LSFVCPWCA (Score-5.604), known as
oncoprotein e7 TAP transporter (Table 1).
We also found the SVM based MHCII-IAb peptide regions, 28-ESSAEDLRT,
2-SHMAEPQRH, 7-PQRHKILCV, 4-MAEPQRHKI, (optimal score is 0.869); MHCII-IAd
peptide regions, 37-LQQLFLSTL, 42-LSTLSFVCP, 25-LTVESSAED, 39-QLFLSTLSF,
(optimal score is 0.466); MHCII-IAg7 peptide regions , 2-SHMAEPQRH,
46-SFVCPWCAT, 17-CKCDGRIEL , 24-ELTVESSAE, (optimal score is 1.207); and MHCII-
RT1.B peptide regions, 26-TVESSAEDL, 29-SSAEDLRTL, 36-TLQQLFLST, 35-RTLQQLFLS,
(optimal score is 0.938) which represented predicted binders from oncoprotein (Table 2). The predicted binding
affinity is normalized by the 1% fractil. The MHC peptide binding is predicted
using neural networks trained on C terminals of known epitopes. In analysis
predicted MHC/peptide binding is a log-transformed value related to the IC50
values in nM units. These MHC binding peptides are sufficient for eliciting the
desired immune response. Predicted MHC binding regions in an antigen sequence
and there are directly associated with immune reactions, in analysis we found
the MHCI and MHCII binding regions.
IV.
Discussion
Gomase (2007)
method, B-EpiPred Server, Hopp and Woods, Welling, Parker, Kolaskar and
Tongaonkar antigenicity scales were
designed to predict the locations of antigenic determinants in Human
papillomavirus oncoprotein. Oncoprotein shows beta sheets regions, which are
high antigenic response than helical region of this peptide and shows highly
antigenicicity (Figures 1-5). We
also found the Sweet hydrophobicity, Kyte & Doolittle hydrophobicity,
Abraham & Leo , Bull & Breese hydrophobicity, Guy, Miyazawa
hydrophobicity, Roseman hydrophobicity, Cowan HPLC pH7.5 hydrophobicity, Rose
hydrophobicity, Eisenberg hydrophobicity, Manavalan hydrophobicity, Black
hydrophobicity, Fauchere hydrophobicity, Janin hydrophobicity, Rao & Argos
hydrophobicity, Wolfenden hydrophobicity, Wilson HPLC hydrophobicity, Cowan
HPLC pH3.4, Rf mobility hydrophobicity, Chothia hydrophobicity scales. Theses
scales are essentially a hydrophilic index, with apolar residues assigned
negative values (Figures 7-26). In
this assay we predicted the binding affinity of Human papillomavirus
oncoprotein e7 having 56 amino acids, which shows 49 nonamers. Small peptide
regions found as 9-RHKILCVCC (score 6.186), 34-LRTLQQLFL (Score- 6.091),
31-AEDLRTLQQ (Score- 5.979), 8-QRHKILCVC (Score- 5.960), 45-LSFVCPWCA
(Score-5.604), known
Table 1. TAP Peptide binders
of oncoprotein
e7.
|
Peptide Rank
|
Start Position
|
Sequence
|
Score
|
Predicted
Affinity
|
|
1
|
9
|
RHKILCVCC
|
6.186
|
High
|
|
2
|
34
|
LRTLQQLFL
|
6.091
|
High
|
|
3
|
31
|
AEDLRTLQQ
|
5.979
|
Intermediate
|
|
4
|
8
|
QRHKILCVC
|
5.960
|
Intermediate
|
|
5
|
45
|
LSFVCPWCA
|
5.604
|
Intermediate
|
|
6
|
5
|
AEPQRHKIL
|
5.598
|
Intermediate
|
|
7
|
7
|
PQRHKILCV
|
5.429
|
Intermediate
|
|
8
|
39
|
QLFLSTLSF
|
5.326
|
Intermediate
|
|
9
|
17
|
CKCDGRIEL
|
5.205
|
Intermediate
|
|
10
|
37
|
LQQLFLSTL
|
4.263
|
Intermediate
|
|
11
|
46
|
SFVCPWCAT
|
4.062
|
Intermediate
|
|
12
|
29
|
SSAEDLRTL
|
4.059
|
Intermediate
|
|
13
|
42
|
LSTLSFVCP
|
3.951
|
Intermediate
|
|
14
|
40
|
LFLSTLSFV
|
3.770
|
Intermediate
|
|
15
|
14
|
CVCCKCDGR
|
3.733
|
Intermediate
|
|
16
|
4
|
MAEPQRHKI
|
3.456
|
Intermediate
|
|
17
|
30
|
SAEDLRTLQ
|
3.435
|
Intermediate
|
|
18
|
10
|
HKILCVCCK
|
3.276
|
Intermediate
|
|
19
|
1
|
GSHMAEPQR
|
3.174
|
Intermediate
|
|
20
|
33
|
DLRTLQQLF
|
3.155
|
Intermediate
|
*Optimal
Score for given MHC binder in Mouse.
as oncoprotein e7 TAP
transporter. Adducts of MHC and peptide complexes are the ligands for T cell
receptors (TCR) (Table 1). MHC
molecules are cell surface glycoproteins, which take active part in host immune
reactions and involvement of MHC class-I and MHC II in response to almost all
antigens (Table 2). Kolaskar and
Tongaonkar antigenicity are the sites of molecules that are recognized by
antibodies of the immune system for the oncoprotein e7, analysis shows epitopes present in the Human papillomavirus the desired immune response (Table 3). The region of maximal
hydrophilicity is likely to be an antigenic site, having hydrophobic
characteristics, because C- terminal regions of oncoprotein is solvent
accessible and unstructured, antibodies against those regions are also likely
to recognize the native protein. For the prediction of antigenic determinant
site of oncoprotein, we got eighteen antigenic determinant sites in the
sequence. The highest pick is recorded between sequence of AA in the region are
‘10-HKILCVCCKCD-20, 24-ELTVESS-30’ (Table
3). We also found the SVM based MHCII-IAb peptide regions, 28-ESSAEDLRT,
2-SHMAEPQRH, 7-PQRHKILCV, 4-MAEPQRHKI, (optimal score is 0.869); MHCII-IAd
peptide regions, 37-LQQLFLSTL, 42-LSTLSFVCP, 25-LTVESSAED, 39-QLFLSTLSF,
(optimal score is 0.466); MHCII-IAg7 peptide regions , 2-SHMAEPQRH,
46-SFVCPWCAT, 17-CKCDGRIEL , 24-ELTVESSAE, (optimal score is 1.207); and MHCII-
RT1.B peptide regions, 26-TVESSAEDL, 29-SSAEDLRTL, 36-TLQQLFLST, 35-RTLQQLFLS,
(optimal score is 0.938) which represented predicted binders from oncoprotein (Table 2). The average propensity for
the oncoprotein is found to be above 1.0350 (Figure- 5). All residues having above 1.0 propensity are always
potentially antigenic (Table 3). The
predicted segments in oncoprotein are ‘10-HKILCVCCKCD-20, 24-ELTVESS-30’.
Fragment identified through this approach tend to be high-efficiency binders,
which is a lagers percentage of their atoms are directly involved in binding as
compared to larger molecules.
V. Conclusion
Human papillomavirus oncoprotein involved multiple
antigenic components to direct and empower the immune system to protect the
host from infection. MHC molecules are cell surface proteins, which take active
part in host immune reactions and involvement of MHC class in response to
almost all antigens and it give effects on specific sites. Predicted MHC
binding regions acts like red flags for antigen specific and generate immune
response against the parent antigen. So a small fragment of antigen can induce
immune response against whole antigen. This theme is implemented in designing
subunit and synthetic peptide vaccines. The sequence analysis method is allows
potential drug targets to identify active sites, which form antibodies against
or plant diseases. The method integrates prediction of peptide MHC class
binding; proteosomal C terminal cleavage and TAP transport efficiency.
Antigenic epitopes of oncoprotein are important antigenic determinants against
the various toxic reactions and viral infections.
Table 2. Peptide binders to
MHCII molecules of oncoprotein e7.
|
Prediction
method
|
Rank
|
Sequence
|
Residue No.
|
Peptide Score
|
|
ALLELE: I-Ab
|
1
|
ESSAEDLRT
|
28
|
0.869
|
|
ALLELE: I-Ab
|
2
|
SHMAEPQRH
|
2
|
0.683
|
|
ALLELE: I-Ab
|
3
|
PQRHKILCV
|
7
|
0.415
|
|
ALLELE: I-Ab
|
4
|
MAEPQRHKI
|
4
|
0.337
|
|
ALLELE: I-Ad
|
1
|
LQQLFLSTL
|
37
|
0.466
|
|
ALLELE: I-Ad
|
2
|
LSTLSFVCP
|
42
|
0.357
|
|
ALLELE: I-Ad
|
3
|
LTVESSAED
|
25
|
0.330
|
|
ALLELE: I-Ad
|
4
|
QLFLSTLSF
|
39
|
0.327
|
|
ALLELE: I-Ag7
|
1
|
SHMAEPQRH
|
2
|
1.207
|
|
ALLELE: I-Ag7
|
2
|
SFVCPWCAT
|
46
|
1.176
|
|
ALLELE: I-Ag7
|
3
|
CKCDGRIEL
|
17
|
0.961
|
|
ALLELE: I-Ag7
|
4
|
ELTVESSAE
|
24
|
0.808
|
|
ALLELE: RT1.B
|
1
|
TVESSAEDL
|
26
|
0.938
|
|
ALLELE: RT1.B
|
2
|
SSAEDLRTL
|
29
|
0.696
|
|
ALLELE: RT1.B
|
3
|
TLQQLFLST
|
36
|
0.563
|
|
ALLELE: RT1.B
|
4
|
RTLQQLFLS
|
35
|
0.503
|
*Optimal Score for given MHC
II peptide binder in Mouse.
Table 3. Antigenic
epitopes from oncoprotein e7.
|
No.
|
Start
position
|
End
position
|
Peptide
|
Peptide
length
|
|
1
|
10
|
20
|
HKILCVCCKCD
|
11
|
|
2
|
24
|
30
|
ELTVESS
|
7
|
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