Prediction of Protein-Protein Interactions with
LSTM Deep Learning Model
Talha Burak Alakus
Department of Software Engineering
Kirklareli University
Kirklareli, Turkey
burak.alakuss@gmail.com, talhaburakalakus@klu.edu.tr
Abstract— Protein-protein interactions (PPI) has a vital
role in molecular biology and bioinformatics since they are the
key organisms which give information about cellular, its
structure and its functions. In recent years many methods and
techniques are proposed in order to perform PPI’s yet they are
suffered from operational time, and large costs as well as low
prediction accuracy. In this study, we performed a deep
learning approach to resolve these problems. To do that we
introduced a LSTM architecture to predict protein-protein
interactions by applying both ProtVec and protein signatures
methods. VCP (valosin-containing protein) which is associated
with H. Pylori is considered in this work. The performance of
the method determined by log-loss, ROC, and classification
accuracy. The proposed method showed a good predictive
ability yet there is still more works need to be performed to
improve the results of PPI prediction studies with respect to
deep learning and machine learning approaches.
Keywords—protein-protein interaction, deep learning,
bioinformatics, prediction.
I. INTRODUCTION
Protein composed of different types of amino acids
which merge together and create a 3-dimensional
structure. Protein can be thought of as a functional part
of the cell. They are responsible for the metabolic
activities of an organism. Yet all of these processes require
interaction between proteins [1]. It’s a well-known fact that
PPI’s are responsible for the function and form of all
organisms [2]. Protein-protein interaction studies are
becoming popular since analyzing proteins give valuable
information about bio-medical functions, complexes and
metabolic cycles. Determining the protein-protein
interactions can be helpful to specify the cancer-related
cells and their networks and other diseases [3].
In order to perform PPI’s, there are two types of
methods existed: Computational and experimental
(biomedical) approaches. Biomedical approaches include
yeast two-hybrid screening (Y2Hs) [4], tandem affinity
purification (TAP) [5], nuclear magnetic resonance (NMR)
[6], and mass spectrometry protein complex identification
(MSPCI) [7]. All of these methods produce a great number
of data during experiment thus they are all require a solid
lab-work and costly laboratory and its equipment. Besides,
the results of protein-protein interactions are highly based
on experimental approaches so it depends on the chemicals
and their metabolic activities. This makes the accuracy
changeable with respect to genome-based methods. On the
other hand, computational methods include machine
learning approaches and network theory metrics.
978-1-7281-3789-6/19/$31.00 ©2019 IEEE
Ibrahim Turkoglu
Department of Software Engineering
Firat University
Elazig, Turkey
iturkoglu@firat.edu
Machine learning algorithms (SVM (support vector
machines), k-NN (k nearest neighbour), RF (random forest),
DT (decision trees) performed an efficient task in data
mining studies yet they cannot find hidden features and they
have a lack of ability to extract the key features when
protein data is big. Furthermore, it requires an amount of
time and quality equipment to process. In recent years’
development of artificial intelligence systems make deep
learning approaches more popular. The main reason behind
that is the data is big nowadays and technology allows
researchers to perform studies more influential and rapid
[8]. Deep learning methods are efficient to extract high-
dimensional and non-linear features from not only protein
sequences but also other fields including real-world
applications, image detection, pattern recognition [9,10]. In
order to perform deep learning and obtain a great
performance in PPI’s analysis, it is needed to combine
different modalities (structural, 1st and 2nd order similarity)
from the protein network [3]. Also, researches should
determine the protein families to specify the protein
interactions.
In this work, we performed a deep learning approach to
predict protein-protein interactions. Firstly, we obtained
VCP data from BioGRID dataset and determine the protein
groups. After, in order to convert the protein sequences into
numerical values both protein signatures and ProtVec
methods were applied. In the last section of the work, LSTM
model was used to classify and predict the protein
interactions. The results of both protein signature-based and
ProtVec based features were compared in the expectation
that to determine the best approach. The performance of the
LSTM was determined the log-loss score, ROC curve
values, and classification accuracy. It is essential to analyze
protein-protein interactions to comprehend the activities and
biology of the organisms. Predicting the interactions
between protein networks is valuable for understanding the
functions of the proteins, their environment, and their
molecular compositions.
The remainder of the paper is organized as follows. In
Section II, we mentioned the PPIs studies in the literature.
The methods, prediction scores and the data were shared in
those sections. In Section III, material and methods of the
proposed method have given. We specified VCP data and
background information. Also, in that section, protein
signature and ProtVec methods, and LSTM deep learning
model were clarified. Section IV presents the prediction
results of the proposed method.
Besides, the performance of the LSTM model is determined
in here including log-loss scores and ROC curve values.
Lastly, the study is concluded in Section V.
II. RELATED WORKS
In this section, computational based PPI studies
including machine learning and deep learning methods in
the literature have been examined and explained.
In the study of [11], researchers tried to predict protein-
protein interaction zones based on machine learning
algorithms. In order to classify the zones, they aimed to use
Radial Basis Functional Neural Network classifier. In order
to convert protein sequences into the numerical
representations, frequencies of each amino acid sequences
were calculated. After, in the feature extraction phase,
relative entropy was calculated and totally 1000 features
were obtained from frequencies. Last part of the study,
radial basis classifier was used and weight parameters were
tested to determine the best classification performance. In
conclusion, the F1 score and classification accuracy were
calculated 99%, and 80% respectively. Protein-protein
interactions were determined based on the protein signatures
method in the study of [12]. Researches obtained
Helicobacter pylori protein data from human and mouse.
After the conversion of sequences, SVM (Support Vector
Machine) was applied to predict the interactions. The
proposed method was tested on both Helicobacter pylori,
Escherichia coli, and Saccharomyces cerevisiae to
determine the performance. During the testing process, 10-
fold cross-validation was used and the performance of the
classifier was stated with specificity, accuracy, and
sensitivity. In conclusion best classification accuracy
obtained from Saccharomyces cerevisiae dataset with 80,7%
classification accuracy. The interactions between proteins
were specified with Siamese Neural Network [1]. In the
study, four different datasets were considered and three
different testing methods (C1, C2, and C3) and two various
neural networks were applied. In the first neural network
model protein sequences were converted with protein
signature while in the second neural network, proteins were
composed with ProtVec method. Test procedures were
designated based on the study of [13]. C1 testing procedure
includes all training and testing data. C2 testing procedure
consists of all testing data yet only consider one training
data. On the other hand, C3 only marks all testing data. The
detailed information on the testing procedures can be seen in
[13]. Protein signature method was given the best result for
both C1 and C2 testing procedure with 93,75% and 85,75%
AUC scores respectively. Yet C3 showed the best result on
C3 testing procedure with 73,25% AUC score. Deep
learning is applied with respect to determining protein
interactions [14]. Firstly, protein sequences were
transformed into numerical representations. After 9 various
deep learning models were used to predict the interactions.
The performance of the proposed method was calculated by
finding accuracy, F1 score, and specificity. During the
testing phase, 5-fold cross-validation was applied and the
results were obtained as 95,29%, 95,29%, and 95,48%
respectively. . In the study of [15], protein interactions
predicted based on protein primer sequences. Researchers
applied both CNN (Convolutional Neural Network) and
LSTM (Long-Short Term Memory) to specify the
interactions. Three various features were obtained from
protein sequences including semantic relations, motifs, and
long-short term relations between proteins. Proposed
method’s performance was determined with 5-fold cross-
validation and average classification accuracy was found
98,78%. At the end of the study, researchers indicated that
deep learning is a powerful tool to inspect PPI’s.
III. MATERIAL AND METHODS
A. VCP and BioGRID
In this study, we obtained VCP protein data from
BioGRID (Biological General Repository for Interaction
Datasets) [16]. BioGRID is an interaction repository for
protein and genetic interactions. It consists of nearly two
million protein interactions data and can be accessed via its
web page.VCP also is known as p97 in mammals and
CDC48 in Saccharomyces cerevisiae is an ATPase enzyme
and encoded by the VCP gene in humans. VCP is a member
of the AAA family of proteins. Fig. 1 shows the typical
VCP. It has a role on protein degradation, DNA repair,
DNA replication, and intracellular membrane fusion. Also,
it affects the regulation of the cell cycle. It has a
homohexameric complex which allows interacting of
different kinds of cofactors. Mutations in this gene cause
many illnesses and diseases including ALS (amyotrophic
lateral sclerosis), CMT (Charcot Marie Tooth), etc. [17].
Fig.1. Valosin containing protein in human [18].
According to the current information of BioGRID, there are
1290 physical interactions exists between VCP and other
proteins. In order to use VCP to determine the PPI with
computational methods, firstly protein sequences were
converted into numerical values. To do that, we applied two
different methods: Protein signature and ProtVec. The
detailed information of all them can be seen in the next
subsections.
B. Protein Signature
Protein signature was developed to encode the protein
sequences into the numerical representations. With this way,
sequences can be transformed into the vector and can give
information to distinguish the binding and non-binding
protein pairs.
Protein signature was advanced based on signature
molecular descriptor [19,20]. The calculation of the
signature has given below in Equation 1 [12];

( )=∑ (1)

In Equation 1, represents the amino acid sequence and

( ) shows the length of that amino acid. is the number
of occurrences in given amino acid. specifies the vector in
the signature space. Protein signature includes amino acid
and its possible neighbours thus, a signature space consists
of all possible signatures. Consider the six-letter amino acid
sequence as an example of MTLVVL. Signatures will be
determined based on three monomer units, and there are
four three monomer units as signatures in that sequence:
MTL, TLV, LVV, VVL. Each unit (signature) has a root
and two neighbours which will be ordered alphabetically.
Thus, the signatures are, T(LM), L(TV), V(LV), and
V(LV) and finally the signature of ( ) =
( ) + ( ) + 2V( ).
In order to use VCP data for deep learning process, one
of the methods that we applied is the signature method
which is helpful to convert the letter sequences to numeric
values. It provided a vector for the classification and
processing for deep learning approach.
C. ProtVec
Using letters, words, and in general nominal values as an
input for feature, vectors can cause problems in machine
learning and deep learning since there is no order in nominal
values. Typically, in order to convert nominal values to
numbers, a word embedding method applied. The aim of the
embedding’s is to reduce the dimension of vector space and
converts the words or letters into a meaningful feature. In
accordance with this information, researches in [21]
developed a word embedding method for protein sequences
and called ProtVec. Proteins were decomposed into to
trimers like three- gram method, and ProtVec is learned for
each word within its surrounding neighbourhood. Fig. 2,
shows the protein-splitting process for obtaining the training
data. With that method, proteins which have similar
physiochemical properties affiliate. Detailed information of
ProtVec can be found at [21].
Fig. 2. Protein splitting process for ProtVec [21].
For converting success of ProtVec, we also applied this
method to transform VPC data to numbers. With that way,
we aimed to compare the performances of two different
methods with respect to the selected deep learning model.
D. LSTM Deep Learning Model
LSTM is a deep learning model developed based on
recurrent neural networks in 1997 [22]. LSTM model is
generally used in many applications including speech
processing, music composition, abstract creations, word
completion, etc. It is a gradient-based learning algorithm
and developed to aim the solve back-flow problems. LSTM
model includes information from the outside of normal flow
of the recurrent neural network in a gated cell. With this
cell, information can be stored, can be read and can be
written. Gates in the model determine which information
will be stored or will be used. These gates were called as
forget gates and it solves the vanishing gradient problem of
recurrent neural networks. Detailed information about
LSTM can be found at [22]. Our proposed method includes
LSTM for prediction of protein- protein interactions.
IV. RESULTS AND DISCUSSION
We developed a LSTM model for protein interaction in
that work. We only considered the first 400 lengths of
sequence of each protein as an input for LSTM classifier.
Before the prediction phase, each protein sequences have
already converted to numerical values. Our model includes
4 1D convolutional layers, 4 pooling layers with average
pooling, 1 LSTM layer and 1 fully connected layer with
Softmax with 1024 neurons. The detailed LSTM model can
be seen in Fig. 3 below.

Fig. 3. LSTM model used in this work.

 According to Figure 3, the first two convolution layers
have 16 filters with a size of 2x1. In the first two pooling
layers’ average value of each input has been calculated with
the number of 32 filters with the size of 2x1 like in
convolutional layers. Size of each filter is the same in the
network only the number of kernels has been changed to
double after the first four layers. After, LSTM was applied
with the size of 512 LSTM units. Fully connected layer has
1024 neurons like Softmax layer which is a classification
layer. Protein sequences were encoded into the numbers
with two different methods: protein signature and ProtVec.
We considered each method to determine the best encoding
technique with respect to the proposed method. The general
structure of the proposed method has given in Fig.4.

Fig. 5. Log-loss score of ProtVec method.

Fig. 4. General structure of the proposed method.

After developing of LSTM model, 400 lengths of protein

sequences were given in the network in order to predict the
protein interactions. Both protein signature and ProtVec
based sequences performed different results and their scores
were given in Table 1. Table 1 shows the classification
accuracies, log-loss scores, and ROC values of each
computational methods based on LSTM network.
Fig. 5. Log-loss score of protein signature method.
TABLE I. PERFORMANCE OF BOTH PROTEIN ENCODING METHODS
BASED ON VARIOUS CRITERIA.
Besides, based on the ROC values both sensitivity and
Encoding Method
Classification Log-Loss ROC specificity values can be calculated. In the ROC curve, the
Accuracy Score Values y- axis represents the sensitivity while the x-axis shows
Protein Signature 86% 0,1508 84% the1- specificity. Table 2 shows both specificity and
sensitivity values for all methods with respect to ROC
ProtVec 92% 0,0834 95%
values.

According to Table 1, ProtVec shows a slightly better TABLE II. SPECIFICITY AND SENSITIVITY VALUES FOR ENCODING
performance than the protein signature method in all METHODS.
criteria. Classification accuracy for ProtVec calculated as
Encoding
92% while protein signature classifies the protein Sensitivity Specificity
Method
interactions with 86% accuracy. The main reason behind
Protein
that is ProtVec is a better tool for encoding protein 84% 91%
Signature
sequences with given circumstances. Also, the log-loss
score for ProtVec is better than the protein signature. Log- ProtVec 95% 93%
loss is a beneficial way to determine the testing and training
score in deep learning and machine learning applications. It As can be seen in Table 2, true positive rates for ProtVec is
gives the 0 scores when the perfect classification (100%) greater than the protein signature technique. Likewise, false
obtained. Fig. 5 and Fig. 6 shows the approximate graphical positive rate also gives better performance with 93%
representation of each method of log-loss scores. accuracy.
 In the conclusion, the proposed method is compared
with some of the existing works in the literature to show the
performance of deep learning model. Table 3 remarks the
comparison results.
TABLE III. COMPARISON RESULTS OF THE STUDIES.
Reference Classification Accuracy Method
11 80% NN
12 80,7% SVM
13 93,75% SVM
14 95,29% DNN
15 98,78% LSTM
This work 92% LSTM
As can be seen in Table 3, in [11-13] authors applied
machine learning algorithms to determine protein
interactions. The average classification performance is
calculated as 84,8% for all three references. On the other,
including this work, both authors in [14,15] applied deep
learning methods. Using a deep learning technique
determines the protein interactions with 95,3% average
accuracy. Deep learning algorithms generate more
successful results than machine learning techniques.
V. CONCLUSION
In this work, a deep learning model for prediction of
protein- protein interaction was proposed. During the study,
VCP data was used to determine the interaction network
with other proteins. In the first stage, protein sequences
were transformed into numerical representations with two
different methods: protein signature and ProtVec. After,
numerical values were normalized to [0,1] range in the
preprocessing phase. In order to predict the interactions,
LSTM model was evaluated with different parameters. Both
protein signature and ProtVec based protein sequences were
used as an input for the LSTM model and the model’s
performance was determined with classification accuracy,
log-loss error rate and ROC values. Both methods gave
promising results and ProtVec gave a slightly better
prediction with 92% accuracy. It is indicated that deep
learning is a powerful tool for PPIs studies yet performance
highly depends on the encoding methods and deep learning
model’s parameters.
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