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1.  Protein Complex Discovery by Interaction Filtering from Protein Interaction Networks Using Mutual Rank Coexpression and Sequence Similarity 
BioMed Research International  2015;2015:165186.
The evaluation of the biological networks is considered the essential key to understanding the complex biological systems. Meanwhile, the graph clustering algorithms are mostly used in the protein-protein interaction (PPI) network analysis. The complexes introduced by the clustering algorithms include noise proteins. The error rate of the noise proteins in the PPI network researches is about 40–90%. However, only 30–40% of the existing interactions in the PPI databases depend on the specific biological function. It is essential to eliminate the noise proteins and the interactions from the complexes created via clustering methods. We have introduced new methods of weighting interactions in protein clusters and the splicing of noise interactions and proteins-based interactions on their weights. The coexpression and the sequence similarity of each pair of proteins are considered the edge weight of the proteins in the network. The results showed that the edge filtering based on the amount of coexpression acts similar to the node filtering via graph-based characteristics. Regarding the removal of the noise edges, the edge filtering has a significant advantage over the graph-based method. The edge filtering based on the amount of sequence similarity has the ability to remove the noise proteins and the noise interactions.
PMCID: PMC4322317
2.  Natural Biased Coin Encoded in the Genome Determines Cell Strategy 
PLoS ONE  2014;9(8):e103569.
Decision making at a cellular level determines different fates for isogenic cells. However, it is not yet clear how rational decisions are encoded in the genome, how they are transmitted to their offspring, and whether they evolve and become optimized throughout generations. In this paper, we use a game theoretic approach to explain how rational decisions are made in the presence of cooperators and competitors. Our results suggest the existence of an internal switch that operates as a biased coin. The biased coin is, in fact, a biochemical bistable network of interacting genes that can flip to one of its stable states in response to different environmental stimuli. We present a framework to describe how the positions of attractors in such a gene regulatory network correspond to the behavior of a rational player in a competing environment. We evaluate our model by considering lysis/lysogeny decision making of bacteriophage lambda in E. coli.
PMCID: PMC4121144  PMID: 25090629
3.  Generalized Baum-Welch Algorithm Based on the Similarity between Sequences 
PLoS ONE  2013;8(12):e80565.
The profile hidden Markov model (PHMM) is widely used to assign the protein sequences to their respective families. A major limitation of a PHMM is the assumption that given states the observations (amino acids) are independent. To overcome this limitation, the dependency between amino acids in a multiple sequence alignment (MSA) which is the representative of a PHMM can be appended to the PHMM. Due to the fact that with a MSA, the sequences of amino acids are biologically related, the one-by-one dependency between two amino acids can be considered. In other words, based on the MSA, the dependency between an amino acid and its corresponding amino acid located above can be combined with the PHMM. For this purpose, the new emission probability matrix which considers the one-by-one dependencies between amino acids is constructed. The parameters of a PHMM are of two types; transition and emission probabilities which are usually estimated using an EM algorithm called the Baum-Welch algorithm. We have generalized the Baum-Welch algorithm using similarity emission matrix constructed by integrating the new emission probability matrix with the common emission probability matrix. Then, the performance of similarity emission is discussed by applying it to the top twenty protein families in the Pfam database. We show that using the similarity emission in the Baum-Welch algorithm significantly outperforms the common Baum-Welch algorithm in the task of assigning protein sequences to protein families.
PMCID: PMC3869655  PMID: 24376498
4.  Construction of random perfect phylogeny matrix 
Interest in developing methods appropriate for mapping increasing amounts of genome-wide molecular data are increasing rapidly. There is also an increasing need for methods that are able to efficiently simulate such data.
Patients and methods
In this article, we provide a graph-theory approach to find the necessary and sufficient conditions for the existence of a phylogeny matrix with k nonidentical haplotypes, n single nucleotide polymorphisms (SNPs), and a population size of m for which the minimum allele frequency of each SNP is between two specific numbers a and b.
We introduce an O(max(n2, nm)) algorithm for the random construction of such a phylogeny matrix. The running time of any algorithm for solving this problem would be Ω (nm).
We have developed software, RAPPER, based on this algorithm, which is available at
PMCID: PMC3170006  PMID: 21918630
perfect phylogeny; minimum allele frequency (MAF); tree; recursive algorithm
5.  A pairwise residue contact area-based mean force potential for discrimination of native protein structure 
BMC Bioinformatics  2010;11:16.
Considering energy function to detect a correct protein fold from incorrect ones is very important for protein structure prediction and protein folding. Knowledge-based mean force potentials are certainly the most popular type of interaction function for protein threading. They are derived from statistical analyses of interacting groups in experimentally determined protein structures. These potentials are developed at the atom or the amino acid level. Based on orientation dependent contact area, a new type of knowledge-based mean force potential has been developed.
We developed a new approach to calculate a knowledge-based potential of mean-force, using pairwise residue contact area. To test the performance of our approach, we performed it on several decoy sets to measure its ability to discriminate native structure from decoys. This potential has been able to distinguish native structures from the decoys in the most cases. Further, the calculated Z-scores were quite high for all protein datasets.
This knowledge-based potential of mean force can be used in protein structure prediction, fold recognition, comparative modelling and molecular recognition. The program is available at
PMCID: PMC2821318  PMID: 20064218
6.  Global haplotype partitioning for maximal associated SNP pairs 
BMC Bioinformatics  2009;10:269.
Global partitioning based on pairwise associations of SNPs has not previously been used to define haplotype blocks within genomes. Here, we define an association index based on LD between SNP pairs. We use the Fisher's exact test to assess the statistical significance of the LD estimator. By this test, each SNP pair is characterized as associated, independent, or not-statistically-significant. We set limits on the maximum acceptable proportion of independent pairs within all blocks and search for the partitioning with maximal proportion of associated SNP pairs. Essentially, this model is reduced to a constrained optimization problem, the solution of which is obtained by iterating a dynamic programming algorithm.
In comparison with other methods, our algorithm reports blocks of larger average size. Nevertheless, the haplotype diversity within the blocks is captured by a small number of tagSNPs. Resampling HapMap haplotypes under a block-based model of recombination showed that our algorithm is robust in reproducing the same partitioning for recombinant samples. Our algorithm performed better than previously reported models in a case-control association study aimed at mapping a single locus trait, based on simulation results that were evaluated by a block-based statistical test. Compared to methods of haplotype block partitioning, we performed best on detection of recombination hotspots.
Our proposed method divides chromosomes into the regions within which allelic associations of SNP pairs are maximized. This approach presents a native design for dimension reduction in genome-wide association studies. Our results show that the pairwise allelic association of SNPs can describe various features of genomic variation, in particular recombination hotspots.
PMCID: PMC2749056  PMID: 19712447
7.  Impact of residue accessible surface area on the prediction of protein secondary structures 
BMC Bioinformatics  2008;9:357.
The problem of accurate prediction of protein secondary structure continues to be one of the challenging problems in Bioinformatics. It has been previously suggested that amino acid relative solvent accessibility (RSA) might be an effective factor for increasing the accuracy of protein secondary structure prediction. Previous studies have either used a single constant threshold to classify residues into discrete classes (buries vs. exposed), or used the real-value predicted RSAs in their prediction method.
We studied the effect of applying different RSA threshold types (namely, fixed thresholds vs. residue-dependent thresholds) on a variety of secondary structure prediction methods. With the consideration of DSSP-assigned RSA values we realized that improvement in the accuracy of prediction strictly depends on the selected threshold(s). Furthermore, we showed that choosing a single threshold for all amino acids is not the best possible parameter. We therefore used residue-dependent thresholds and most of residues showed improvement in prediction. Next, we tried to consider predicted RSA values, since in the real-world problem, protein sequence is the only available information. We first predicted the RSA classes by RVP-net program and then used these data in our method. Using this approach, improvement in prediction was also obtained.
The success of applying the RSA information on different secondary structure prediction methods suggest that prediction accuracy can be improved independent of prediction approaches. Thus, solvent accessibility can be considered as a rich source of information to help the improvement of these methods.
PMCID: PMC2553345  PMID: 18759992
8.  A tale of two symmetrical tails: Structural and functional characteristics of palindromes in proteins 
BMC Bioinformatics  2008;9:274.
It has been previously shown that palindromic sequences are frequently observed in proteins. However, our knowledge about their evolutionary origin and their possible importance is incomplete.
In this work, we tried to revisit this relatively neglected phenomenon. Several questions are addressed in this work. (1) It is known that there is a large chance of finding a palindrome in low complexity sequences (i.e. sequences with extreme amino acid usage bias). What is the role of sequence complexity in the evolution of palindromic sequences in proteins? (2) Do palindromes coincide with conserved protein sequences? If yes, what are the functions of these conserved segments? (3) In case of conserved palindromes, is it always the case that the whole conserved pattern is also symmetrical? (4) Do palindromic protein sequences form regular secondary structures? (5) Does sequence similarity of the two "sides" of a palindrome imply structural similarity? For the first question, we showed that the complexity of palindromic peptides is significantly lower than randomly generated palindromes. Therefore, one can say that palindromes occur frequently in low complexity protein segments, without necessarily having a defined function or forming a special structure. Nevertheless, this does not rule out the possibility of finding palindromes which play some roles in protein structure and function. In fact, we found several palindromes that overlap with conserved protein Blocks of different functions. However, in many cases we failed to find any symmetry in the conserved regions of corresponding Blocks. Furthermore, to answer the last two questions, the structural characteristics of palindromes were studied. It is shown that palindromes may have a great propensity to form α-helical structures. Finally, we demonstrated that the two sides of a palindrome generally do not show significant structural similarities.
We suggest that the puzzling abundance of palindromic sequences in proteins is mainly due to their frequent concurrence with low-complexity protein regions, rather than a global role in the protein function. In addition, palindromic sequences show a relatively high tendency to form helices, which might play an important role in the evolution of proteins that contain palindromes. Moreover, reverse similarity in peptides does not necessarily imply significant structural similarity. This observation rules out the importance of palindromes for forming symmetrical structures. Although palindromes frequently overlap with conserved Blocks, we suggest that palindromes overlap with Blocks only by coincidence, rather than being involved with a certain structural fold or protein domain.
PMCID: PMC2474621  PMID: 18547401
9.  Impact of RNA structure on the prediction of donor and acceptor splice sites 
BMC Bioinformatics  2006;7:297.
gene identification in genomic DNA sequences by computational methods has become an important task in bioinformatics and computational gene prediction tools are now essential components of every genome sequencing project. Prediction of splice sites is a key step of all gene structural prediction algorithms.
we sought the role of mRNA secondary structures and their information contents for five vertebrate and plant splice site datasets. We selected 900-nucleotide sequences centered at each (real or decoy) donor and acceptor sites, and predicted their corresponding RNA structures by Vienna software. Then, based on whether the nucleotide is in a stem or not, the conventional four-letter nucleotide alphabet was translated into an eight-letter alphabet. Zero-, first- and second-order Markov models were selected as the signal detection methods. It is shown that applying the eight-letter alphabet compared to the four-letter alphabet considerably increases the accuracy of both donor and acceptor site predictions in case of higher order Markov models.
Our results imply that RNA structure contains important data and future gene prediction programs can take advantage of such information.
PMCID: PMC1526458  PMID: 16772025

Results 1-9 (9)