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A systematic review: B-cell conformational epitope prediction from epitope

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 A Systematic Review: B-Cell Conformational
Epitope Prediction from Epitope Characteristics View

Binti Solihah1,2, Edi Winarko1, Afiahayati1, Sri Hartati1, Moh. Edi Wibowo1
1
Department of Computer Science and Electronic
Universitas Gadjah Mada,
Yogyakarta, Indonesia
2
Department of Informatics,
Faculty of Industrial Technology, Universitas Trisakti,
Jakarta, Indonesia

{binti.solihah, af1a}@mail.ugm.ac.id, {ewinarko, shartati,mediw}@ugm.ac.id

Abstract—B-cell conformational epitope identification is the
crucial issue in vaccinology. Limitation on experimental methods
in the biological side, dataset and availability of computational
resources opens a chance on developing prediction method which
can accelerate epitope identification. A number of methods have
been developed but their performance is still medium. Epitope
prediction is a knowledge-based method. Presenting the
statistical or computational based epitope characteristics together
with epitope prediction method will facilitate the newcomer on
identifying importance feature, improve the existing feature and
propose the new feature. To reach the goal of the review, the
research papers are collected from both epitope analysis research
and epitope prediction methods research. The prediction
methods are evaluated on what characteristics of epitope have
been implemented on feature representation and are shown in a
mapping table.
Keywords— conformational epitope prediction method, epitope
characteristics, 3D structure based feature
I. INTRODUCTION
B-cell epitope identification is needed in the modern
vaccine development. B cell epitope is part of the antigen that
interacts with the paratope of antibody. About 90% of B-cell
epitope is conformational epitope that is adjacent spatially but
located in separated segment of primary sequence[1]. B-cell
epitope data is extracted from Antigen-Antibody complexes
from X-ray crystallography. The data represents the
coordinate record of its atom components. These coordinate
can not be used directly to identify epitope of the antigen. The
availability of 3D structure of Antigen-Antibody complex in
Protein Data Bank (PDB) supports biology research [2] and
makes it possible to know epitope characteristics and to reveal
new aspects in molecular immunology identification [3]. More
general description about prediction method on B-cell
conformational epitope from database point of view,
algorithms, web server implementation, and its application on
problem-solving is discussed in [4,5,6].
This literature review focus on the discussion of the
relationship between epitope characteristics extracted from the
computational analysis, feature representation and the
accuracy of epitope prediction method. The goal of the review
is to identify possibility to improve feature representation and
to identify problems in the development of epitope prediction
method. To achieve the aim of the review, a systematic
literature review is conducted by the guideline of Kitchenham
and Charters[7]. The discussion is started with the related
work and continued with the explanation of methodology. The
next section is the result of review and conclusion is given at
the end of the review.
II. RELATED WORK
There are two research areas related to this review, i.e.
research on the computational analysis of epitope and research
on conformational epitope prediction method. Review on
computational analysis aims to explore the epitope
determinant. Review on conformational epitope prediction
aims to explore the state of the art of methods.
The first paper on conformational epitope is work done by
Hubbard et al.[8]. The next computational analysis conducted
by [3, 9,10,11, 12]. The computational analysis on epitope by
Rubinstein et al. [3] analyzed the physicochemical properties,
structure, and geometric characteristics of epitope. Fifty three
data were selected from 256-row data on the SPIN server. Sun
et al. [9] analyze physicochemical properties (AAIndex) and
structure aspect of epitope characteristics on 161
immunoglobulin complexes. Kringelum et al. [13] analyze the
structure and geometric characteristic including size, shape,
and orientation to the antibody on 107 antigen data from 376
Ag-Ab complexes. Sivalingam and Shepherd [10] identify
discontinuity level of the conformational epitope on 150 Ag-
Ab complexes from the Summary of Antibody Crystal
Structures (SACS) database. Zheng et al. [12] analyze the
deep level of the conformational epitope on 161 protein
sequence from 144 Ag-Ab complexes. Epitope characteristics
from computational analysis affects the feature extraction
selected on the proposed prediction methods.
The Majority of the epitope prediction method use
classification approach to label input residue as epitope or
non-epitope. From the data sample availability, this problem is
categorized as imbalance class problem, where epitope sample
is much less than the non-epitope sample. For example, the
ratio of the epitope to non-epitope exposed residue on [3] is
1:10. Identification of existing conformational epitope
prediction method shows that the early developing methods
ignore imbalance class problem and focus on the developing
of discriminant function on the basis of feature combination.
Methods that use this approach are DiscoTope [1], Pepito [13],
Discotope 2 [14], Epitome [15], Ellipro [4], EPCES [16],
SEPPA [17], and SEPPA 2[18].
The newest approach uses machine learning approach by
Rubinstein et al. [19] and considers the imbalance class
problem, i.e. [20,21,22]. Other than feature and imbalance
class problem, feature selection is one of the open problems to
build effective classifier on epitope prediction. Another
approach that has been applied to epitope prediction method is
a graph-based method, as proposed in[23,24,25]. Besides the
stand-alone model, there is ensemble classifier that combines
several models to gain performance improvement. The first
implementation of ensemble method on epitope prediction is
EPMeta by [26]. This server combines EPSVR, EPCES,
EPITOPIA, SEPPA, PEPITO, and Discotope1.2. Hu et al. [27]
apply ensemble machine learning with several alternatives of
meta-learning.
III. METHODOLOGY
Following the guidance by Kitchenham and Charters [7]
this systematic literature review conduct in three stages:
planning, conducting, and reporting.
A. Planning
The need for systematic review in this research has been
discussed in the Introduction Section. The research question is
composed using PICOC criteria, as shown in Table 1. PICOC
criteria are the extension from its origin (PICO) in the medical
guideline. In Computer Science such as in Software
Engineering, Comparison means what is the intervention
being compared with and Context means what is the context in
which the intervention is delivered [7]. The research questions
(RQ) of this systematic literature review are as follows:
RQ1: What is the epitope characteristic that has been
identified? (motivation: identify epitope characteristic that has
been known).
RQ2: What is the dominant feature of conformational epitope
prediction method? (motivation: Identify strong relevant
feature)
RQ3: What kinds of method are used for conformational
epitope? (motivation: identity strong and weakness of each
method)
RQ4: What are parameters to evaluate prediction
performance?
(motivation: identify parameters to evaluate method
performance).
TABLE 1. PICOC criteria
aspect specification
Population (P) computational analysis on epitope and conformational
epitope prediction
Intervention (I) Epitope characteristic in several aspects, method, and
feature extraction
Comparison(C) n/a
Outcome(O) Problem, Feature,
Relation between epitope characteristic with epitope
prediction performance
Context (C) Literature review on computational and statistical
analysis of epitope
Literature review on B cell conformational epitope.
B. Conducting the review
The first step in conducting the review determines the
search strategy. The keywords for searching are extracted
from RQ. The used keywords to collect literature are B-cell
epitope characteristics, conformational epitope prediction,
and survey on epitope prediction method. After the keywords
are determined, the database of literature is constructed. The
first survey is conducted using Google search to get the most
popular database that contains these subjects. In the second
step, the database is selected based on their reputation. The
selected database are: IEEE explore, NCBI, PLOS, Springer
link, and ScienceDirect.
The next step after search strategy is the study selection.
Study selection conduct using inclusion and exclusion criteria
as follows:
Inclusion criteria:
• Study discussing epitope identification, epitope analysis,
epitope characteristics, and conformational epitope
prediction method.
• Source from cited journal article.
• Study with strong validation and comparison with others
popular method is included.
• The primary study which is published on 2005 or later.
• Prediction method uses data 3D structure of Ag-Ab
complex is included.
Exclusion criteria:
• Epitope identification outside the computational-based
method is excluded.
• Study without strong validation and comparison with
other popular method are excluded.
• Prediction method use feature that is extracted not only
from the 3D structure are excluded.
IV. RESULT AND DISCUSSION
The selection criteria applied to search results gives 5
primary papers and 2 secondary papers on epitope analysis
and 18 primary papers on conformational epitope prediction.
There are 5 papers excluded from the paper on conformational
epitope prediction. The existence of primary papers in epitope
analysis means the papers on the epitope characteristics can be
excluded. The work of Hubbard et al.[11] and Zhang et al.
[28] are categorized as secondary paper. Hubbard introduces
the conformational parameter in native protein structure which
is used as reference in conformational epitope analysis, where evolutionary conservation aspect, the difference result can be
epitope is a special kind of protein-protein interaction. found at [12,9]. Kringelum et al. [11] shown that there is no
Epitope and mimotope have some similar and different significant deviation on amino acid preference between
characteristics[28]. Based on Zhang et al.[28], 5 papers on epitope and non-epitope on the same level of surface
mimotope-based conformational epitope prediction are exposure. The different result from the previous research is the
excluded from the primary paper in conformational epitope effect of difference definition of non-epitope residue.
prediction. Andersen et al.[1] define non-epitope residue as all non-
interacting residue on the antigen. Ofran et al. [30] define non-
A. Epitope characteristics epitope residue as all residue at PDB. Rubinstein et al. [3] just
RQ1: What is the epitope characteristic that have been use non-epitope residue from residue with RSA more than 5%.
identified? Kringelum et al. [11] use only non-epitope from the exposed
residue from the same exposure level. For evolutionary
There are several aspects which are analyzed in epitope conservation value, Zheng et al. [12] shows that the
characteristics: physicochemical, structure, geometric, evolutionary conservation is not significantly lower than
discontinuity level, and deep level. The analysis is conducted exposed residue non-epitope. Sun et al. [9] use AAIndex as
after filtering process. There is no standard on filtering identification parameter of epitope characteristic. AAIndex
criteria. Although the threshold used differs between papers, is proposed by Kawashima et al. [31] consist of 544 indexes. It
the general criteria are (1) Use antigen which is interacted is categorised in 6 categories: helix and turn, sheet
with the antibody (2) remove redundancy (3) data resolution conformation, residue composition, physicochemical,
(4) number of residue on the antigen. Although it is generated hydrophobic and other characteristics. Sun et al. [9] shows that
some dataset, they share many complexes. The identification as much as 21 residue characteristic at AAIndex is proven can
on Rubinstein et al. [3] and Kringelum et al. [11] shows 74% distinguish epitope from non-epitope exposed residue.
data on [3] are used in [11]. A conformational epitope is Table 3. Residual level characteristic of conformational epitope (without
composed of a number of residues that bind to the antibody, so contrary fact)
the epitope residue has two membership level: as residue Characteristic Analysis result Ref.
component and patch member. Epitope also has a unique Accessibility -Exposed on surface [32]
interaction pattern with the antibody, compared with the other -on planar area [3]
protein-protein interaction. Sun et al. [9] categorized the -epitope exist on outer layer of [12]
convex hull and deeper than exposed
parameters to describe the epitope in four perspectives: non-epitope
general characteristics, residual, structural, and interaction Residue pair Pairs of Tyr:Tyr, Cys:Pro, Asn:Tyr, [3]
patterns with an antibody. By considering the membership preference Gly:Tyr, Asp:Pro, Thr:Tyr and
type, these four categories is simplified into three categories. Arg:Tyr dominate in epitope
The general characteristics and structural characteristics of the compare to non-epitope antigen
epitope is at the patch level, so in this study, both parameters surface.
Pairs of Asn:Tyr, His:Tyr and [9]
are categorized as the characteristics of the patch level. Table His:Met dominate epitope
2 shows the identification parameters in each category. A Physicochemical AAIndex of epitope residue and non [9]
detailed explanation of each category is discussed in the next characteristics: epitope surface residue have
sub-section. AAIndex correlation value 0.8 (high
correlation)
Table 2. Identified parameter on each category Secondary Enrich by loop, depleted strand and [3]and [30]
Categorization Identified Parameter structure helix
Residual Characteristics Residue accessibility Polarity Compare to non-epitope residue, [1] [30] [3]
Amino acid Preference epitope residue contain more polar [33][9] [11]
Residue-pair preference and charge amino acid and depleted [34]
AAIndex of hydrophobic amino acid.
Secondary structure Charge Compare to non-epitope residue, [1], [30],
Evolutionary conservation epitope residue contain more charged [3], [33]and
Patch level Characteristics: Epitope size : residue number amino acid. [9]
Sequential continuity hydrophobicity Compare to non-epitope residue, [1], [30],
Geometrics shape epitope residue contain less [3], [33]
Interaction pattern with antibody Epitope-Paratope residue pair hydrophobic amino acid. and [9]
preference
Hydrophobic residue closer to
antibody while hydrophilic core [11]
flanked by charged residue
B. Residual characteristics
Most of the analysis results show their relevance with the
previous research, as shown in Table 3 and lead to specifics C. Epitope characteristics at patch level
characteristics, except for amino acid preference and Detail epitope characteristic at patch level is shown in
evolutionary conservation which shown the existence of Table 5. Generally, the analysis result at patch level shows
contrary fact as shown in Table 4. For the amino acid there is no contrary result. For example, although the filtering
preference, there is a difference between analysis result on criteria on residue number in Sun et al. [9] are greater than in
Kringelum et al. [11] with the previous result in [9,29]. In the Kringelum et al. [11], the analysis result shows that range of
residue number at [11] is covered by [9]. This result shows
that antigen size does not influence the residue number of
epitope. From geometric aspect, result analysis shows the
more specific characteristic of epitope can be identified.
Table 4. Residual level characteristic of conformational epitope
(with contrary fact)
Characteristic Analysis result Reference
Amino acid Contain more Trp, Tyr, Arg and [9]
preference * His and less Cys, Ala and Val
Contain more Gly, Trp, Tyr, His,
Gln, Met [34]
Contain more charged residue:
Asp, Glu, Lys, Arg, His; non- [12]
charge residue: Asn, Gln;
aromatic residue: Tyr
Trp and Tyr dominate the
antigen surface.
Can’t distinguish between [29]
epitope residue and non-epitope
exposed residue but some [11]*
residue is rarely appear.
evolutionary Less conserve than exposed [9]
conservation* residue non epitope
Conservation score not
significantly difference than [12]
exposed residue non epitope
Conformational epitope composed of spatially neighboring
residues which are separated in the primary structure or
sequence. From the analysis result, it is shown that the
conformation is composed of linear segments with variation
length. Sun et al. [9] states that these linear segments may
have a definite role in the antibody binding. This statement
needs further analysis. In windows-based sequential analysis
[10] both epitope and functional epitope are scattered on the
sequence. This finding makes windows-based prediction
method on the primary structure of protein is reasonable to
detect linear segments of B-cell epitope.
D. Epitope characteristics on Ag-Ab Interaction
Analysis on Ag-Ab interaction is still rare nevertheless
Ag-Ab interaction is specific than other protein interaction, as
reinforce by Jackson [35] where interaction between antigen
and antibody occur at side chain not in the main chain. One of
the reasons for this scarcity is researcher’s focus on epitope
exclusively in the beginning so that the interaction with
antibody is ignored. Several characteristics have been
identified are its relative orientation to antibody, Contact with
CDR, AA Preference on CDR, and B Factor. According to
[11], epitope orientation is -30o to 60o to light and heavy
chain antibody. Rubinstein et al. [3] show that 90% area
epitope contact with CDR. CDR contain more Ser and Tyr
with Tyr create more Hydrogen binding, and beta factor on
CDR area is lower than on non-CDR area [36].
E. B-cell conformational epitope prediction methods
RQ2: What is the dominant feature on conformational epitope
prediction method?
The dominant feature on conformational epitope is feature
that represents solvent accessibility. This feature represents
the exposed level of residue. There is some measure can be
used to represent this characteristic: Accessible Surface Area
(ASA), Relative Surface Area (RSA), Half Sphere Exposure
(HSE), and Contact Number (CN). The features derived from
solvent accessibility which is extracted first in the epitope
prediction method are ASA and RSA. These characteristics
can separate exposed residue from buried residue. Other
features derived from other characteristics, such as
physicochemical, geometrics, and evolutionary conservation
are used to calculate antigenicity score of each exposed
residue. The list of epitope characteristics which is used in
prediction method is shown in Table 5.
Table 5. Epitope characteristics in prediction method
Considered epitope characteristics Ref
Accessibility (CN) 1,16
Statistic deviation between epitope 1,14,38
and non-epitope
Accessibility (HSE) 13,14,
Accessibility (ASA ) 37,17,18,22,21
Geometric properties 37
Patch level characteristic 16,17,18,
Physicochemical 18,19,38,21,22
Accessibility (RSA ) 1,16,20,22
structural- geometrical properties 19,20,38,22,
Amino acid composition 20
Evolutionary conservation 20,21,38,
Flexibility 22
Amino acid residue pair 21
The relation between epitope characteristics is still
unknown, some researchers use statistic deviation and
represent this characteristic as propensity score. The first
attempt is conducted by Andersen et al.[1] which propose the
log-odd ratio calculated from the epitope dataset. Andersen’s
log-odd ratio is derived use Gibbs sampling method proposed
in [39]. Kringelum et al. [14] combine the Andersen’s idea
with Sweredoski and Baldi’s idea [13] and propose log-odd
ratio in spatial neighborhood context. Kringelum work [14]
shows that successful attempt to bring epitope characteristics
in spatial context can improve the performance of the method.
RQ3: What kinds of method are used for conformational
epitope?
Identification on existing conformational epitope
prediction method shows that in the beginning, the prediction
method ignores imbalance class problem and focuses on the
developing of discriminant function on the basis of feature
combination. The proposed method that use this approach is
score which is derived from statistic deviation [1] is
comparable with the methods which is combine several
known epitope characteristics, as shown in [16]. Bringing the
propensity score in spatial context as in [14 improves the
performance significantly. Unit patch of residue triangle [17]
is better in describing the local spatial context. Embedding the
epitope characteristic at local spatial context [18] improves the
performance. Applying non-linear classifier such as SVM,
ANN, and Gaussian Mixture at [13] by ignoring imbalance
class does not gain optimal performance. It is caused by the
machine learning weakness such as SVM on imbalance class
problem that is not handled properly.
 Further development of epitope prediction methods, where
the feature evolves to large dimension, the machine learning
approach is more successful than the previous attempt.
Several approaches consider the imbalance class problem,
such as in [20, 21, 22]. Three approaches are used to resolve
imbalance class problem, i.e. data level, algorithm level and
hybrid. On the data level, the method is applied to achieve
balances in both positive class and negative class of data
training. On Zhang et al.[20] imbalance class problem is
solved on data level using bootstrapping to down sample the
negative class randomly. Down sampling approach in
imbalance class potentially eliminates the key feature. On
algorithm level, there are two approaches. The first approach
uses algorithm modification to reduce bias to the majority
group. Zhang et al. [21] propose cost-sensitive boosting to
develop strong classifier from the weak classifier. The second
approach implements one class learning that focuses on the
target group. Ren et al. [22] use algorithm level approach that
use one class classifier method, i.e. positive unlabeled
learning.
On further developments, along with the accumulated
knowledge of the epitope, the number of feature vector
developed rapidly. Other than imbalance class problem,
feature selection is one of the open problems to build effective
classifier on epitope prediction. First attempt to use feature
selection is conducted by Rubinstein [19]. He uses top down
heuristic searches to select 44 immunogenic characteristics.
Zhang et al. [20] use Fisher-Markov Selector and incremental
Feature Selection to find optimal feature. Considering feature
representation and imbalance class problem to solve epitope
prediction gives better model, as shown at [22] where their
approach outperformed SEPPA 2.0, Discotope 2.0 and Ellipro.
The main limitation of this approach is that the feature must
have been known at the beginning of the process. This
condition is not satisfied in real condition, where it is possible
to have new feature after the selection process is ended.
Besides the stand-alone model, there is ensemble classifier
that combines several models to gain performance
improvement. The performance of ensemble model is the best
between the combined model, but still can not achieve the
desirable performance. The first implementation of ensemble
method on epitope prediction is EPMeta [26]. This server
combines EPSVR, EPCES, EPITOPIA, SEPPA, PEPITO, and
Discotope1.2. Hu et al.[27] apply ensemble machine learning
with several alternatives of meta-learning to identify the
relation between the accuracy gain and epitope characteristics
which is considered in prediction method, in this article the
performance of the method is assessed based on characteristics
completeness. The machine learning approach has been
improved significantly. However, it still has limitations on
proposed method and huge room for performance
improvement exists [24].
Other approach that has been applied to epitope prediction
method is a graph-based method, as proposed in [24,25]. Zhao
et al.[24] use Markov Clustering graph algorithm to
distinguish epitope from non-epitope. Zhao et al. [25] use
graph mining to find the coupling sub graph and propose
graph transformation to transfer coupling graph to generic
graph. The coupling graph technique is in line with antigen-
antibody interaction phenomena. The knowledge about
antigen-antibody interaction opens room for the development
of graph-based prediction method such as in [3,11, 36].
RQ4: What parameters are used to evaluate prediction
performance?
There is no agreed upon standard to measure the performance
of prediction method. Researchers use variety combination of
the area under the receiver operating characteristic (ROC)
curve (AUC), accuracy, recall, specificity, sensitivity,
precision, F-Score and MCC. Epitope prediction method is a
classification problem. In the classification problem, the
standard method to measure general performance is the area
under the receiver operating characteristic (ROC) curve
(AUC)[4]. On imbalance class, AUC underestimates the actual
predictive power because it considers prediction that is not
part of any validated epitope as false prediction [3]. Accuracy
(recognition rate) describe recognition rate both positive and
negative sample and effective on balance sample [22]. On
imbalance class, the majority class will achieve better
accuracy. Recall, specificity, and precision reflect the
prediction tendency of the classifier. F-Score is a combination
of precision and recall and effective to measure both on
balance and imbalance sample. MCC is effective on imbalance
sample with the range from +1 to -1 by indication: +1: perfect
prediction, 0: random prediction, -1: totally reverse prediction.
As resume of the existing approach, there is still a limited
number of methods proposed to solve the conformational
epitope prediction. There are some advances have been
achieved on this field of study, but there are still chances to
improve the performance. Considering imbalance class
problem, doing feature selection, improving the features and
integrating them to make strong classifier are main keys to
make effective prediction.
V. CONCLUSSION AND FUTURE WORK
This study identifies the relationship between epitope
characteristic and the performance of prediction method.
There are two research areas that have strong relation with this
study, research on epitope analysis and research on
conformational epitope prediction. There are some epitope
characteristics have been identified in epitope analysis.
However, there is no proposed method that considers all of the
characteristics. This is caused by the difficulty to extract
feature on 3D structure base. To achieve good performance on
epitope prediction there are three main problems must be
solved, i.e. the imbalance class problem, feature extraction,
and the feature selection and integration. The specificity of
epitope-paratope interaction also makes a chance to make a
new approach in epitope prediction or improve the graph
based approach. The number of data sets relatively fixed, but
the feature continues to evolve in line with the new finding on
feature representation of epitope. This condition has new
problem in epitope prediction: if there are new features, are
these features can be incorporated into the classifier.
Considering imbalance class problem and feature selection on
developing algorithm make a chance to improve the accuracy
of prediction gradually.

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