Chen-hsiung Chan

Improving disulfide connectivity prediction with sequential distance between oxidized cysteines

SUMMARY Predicting disulfide connectivity precisely helps towards the solution of protein structure prediction. In this study, a descriptor derived from the sequential distance between oxidized cysteines (denoted as DOC) is proposed. An approach using support vector machine (SVM) method based on weighted graph matching was further developed to predict the disulfide connectivity pattern in proteins. When DOC was applied, prediction accuracy of 63% for our SVM models could be achieved, which is significantly higher than those obtained from previous approaches. The results show that using the non-local descriptor DOC coupled with local sequence profiles significantly improves the prediction accuracy. These improvements demonstrate that DOC, with a proper scaling scheme, is an effective feature for the prediction of disulfide connectivity. The method developed in this work is available at the web server PreCys (prediction of cys-cys linkages of proteins).

Cysteine separations profiles on protein sequences infer disulfide connectivity

MOTIVATION Disulfide bonds play an important role in protein folding. A precise prediction of disulfide connectivity can strongly reduce the conformational search space and increase the accuracy in protein structure prediction. Conventional disulfide connectivity predictions use sequence information, and prediction accuracy is limited. Here, by using an alternative scheme with global information for disulfide connectivity prediction, higher performance is obtained with respect to other approaches. RESULT Cysteine separation profiles have been used to predict the disulfide connectivity of proteins. The separations among oxidized cysteine residues on a protein sequence have been encoded into vectors named cysteine separation profiles (CSPs). Through comparisons of their CSPs, the disulfide connectivity of a test protein is inferred from a non-redundant template set. For non-redundant proteins in SwissProt 39 (SP39) sharing less than 30% sequence identity, the prediction accuracy of a fourfold cross-validation is 49%. The prediction accuracy of disulfide connectivity for proteins in SwissProt 43 (SP43) is even higher (53%). The relationship between the similarity of CSPs and the prediction accuracy is also discussed. The method proposed in this work is relatively simple and can generate higher accuracies compared to conventional methods. It may be also combined with other algorithms for further improvements in protein structure prediction. AVAILABILITY The program and datasets are available from the authors upon request. CONTACT cykao@csie.ntu.edu.tw.

POINeT: protein interactome with sub-network analysis and hub prioritization

BackgroundProtein-protein interactions (PPIs) are critical to every aspect of biological processes. Expansion of all PPIs from a set of given queries often results in a complex PPI network lacking spatiotemporal consideration. Moreover, the reliability of available PPI resources, which consist of low- and high-throughput data, for network construction remains a significant challenge. Even though a number of software tools are available to facilitate PPI network analysis, an integrated tool is crucial to alleviate the burden on querying across multiple web servers and software tools.ResultsWe have constructed an integrated web service, POINeT, to simplify the process of PPI searching, analysis, and visualization. POINeT merges PPI and tissue-specific expression data from multiple resources. The tissue-specific PPIs and the numbers of research papers supporting the PPIs can be filtered with user-adjustable threshold values and are dynamically updated in the viewer. The network constructed in POINeT can be readily analyzed with, for example, the built-in centrality calculation module and an integrated network viewer. Nodes in global networks can also be ranked and filtered using various network analysis formulas, i.e., centralities. To prioritize the sub-network, we developed a ranking filtered method (S3) to uncover potential novel mediators in the midbody network. Several examples are provided to illustrate the functionality of POINeT. The network constructed from four schizophrenia risk markers suggests that EXOC4 might be a novel marker for this disease. Finally, a liver-specific PPI network has been filtered with adult and fetal liver expression profiles.ConclusionThe functionalities provided by POINeT are highly improved compared to previous version of POINT. POINeT enables the identification and ranking of potential novel genes involved in a sub-network. Combining with tissue-specific gene expression profiles, PPIs specific to selected tissues can be revealed. The straightforward interface of POINeT makes PPI search and analysis just a few clicks away. The modular design permits further functional enhancement without hampering the simplicity. POINeT is available at http://poinet.bioinformatics.tw/.

Disulfide connectivity prediction with 70% accuracy using two-level models

Disulfide bridges stabilize protein structures covalently and play an important role in protein folding. Predicting disulfide connectivity precisely helps towards the solution of protein structure prediction. Previous methods for disulfide connectivity prediction either infer the bonding potential of cysteine pairs or rank alternative disulfide bonding patterns. As a result, these methods encode data according to cysteine pairs (pair‐wise) or disulfide bonding patterns (pattern‐wise). However, using either encoding scheme alone cannot fully utilize the local and global information of proteins, so the accuracies of previous methods are limited. In this work, we propose a novel two‐level framework to predict disulfide connectivity. With this framework, both the pair‐wise and pattern‐wise encoding schemes are considered. Our models were validated on the datasets derived from SWISS‐PROT 39 and 43, and the results demonstrate that our models can combine both local and global information. Compared to previous methods, significant improvements were obtained by our models. Our work may also provide insights to further improvements of disulfide connectivity prediction and increase its applicability in protein structure analysis and prediction. Proteins 2006.

Integrated minimum-set primers and unique probe design algorithms for differential detection on symptom-related pathogens

MOTIVATION Differential detection on symptom-related pathogens (SRP) is critical for fast identification and accurate control against epidemic diseases. Conventional polymerase chain reaction (PCR) requires a large number of unique primers to amplify selected SRP target sequences. With multiple-use primers (mu-primers), multiple targets can be amplified and detected in one PCR experiment under standard reaction condition and reduced detection complexity. However, the time complexity of designing mu-primers with the best heuristic method available is too vast. We have formulated minimum-set mu-primer design problem as a set covering problem (SCP), and used modified compact genetic algorithm (MCGA) to solve this problem optimally and efficiently. We have also proposed new strategies of primer/probe design algorithm (PDA) on combining both minimum-set (MS) mu-primers and unique (UniQ) probes. Designed primer/probe set by PDA-MS/UniQ can amplify multiple genes simultaneously upon physical presence with minimum-set mu-primer amplification (MMA) before intended differential detection with probes-array hybridization (PAH) on the selected target set of SRP. RESULTS The proposed PDA-MS/UniQ method pursues a much smaller number of primers set compared with conventional PCR. In the simulation experiment for amplifying 12 669 target sequences, the performance of our method with 68% reduction on required mu-primers number seems to be superior to the compared heuristic approaches in both computation efficiency and reduction percentage. Our integrated PDA-MS/UniQ method is applied to the differential detection on 9 plant viruses from 4 genera with MMA and PAH of 11 mu-primers instead of 18 unique ones in conventional PCR while amplifying overall 9 target sequences. The results of wet lab experiments with integrated MMA-PAH system have successfully validated the specificity and sensitivity of the primers/probes designed with our integrated PDA-MS/UniQ method.

Cliques in mitotic spindle network bring kinetochore-associated complexes to form dependence pathway.

The mitotic spindle is an essential molecular machine for chromosome segregation during mitosis. Achieving a better understanding of its organization at the topological level remains a daunting task. To determine the functional connections among 137 mitotic spindle proteins, a protein–protein interaction network among queries was constructed. Many hub proteins, which connect more than one query and serve as highly plausible candidates for expanding the mitotic spindle proteome, are ranked by conventional degree centrality and a new subnetwork specificity score. Evaluation of the ranking results by literature reviews and empirical verification of SEPT6, a novel top‐ranked hub, suggests that the subnetwork specificity score could enrich for putative spindle‐related proteins. Topological analysis of this expanded network shows the presence of 30 3‐cliques and six 4‐cliques (fully connected subgraphs) that, respectively, reside in eight kinetochore‐associated complexes, of which seven are evolution conserved. Notably, these complexes strikingly form dependence pathways for the assembly of the kinetochore complex. These analyses indicate the feasibility of using network topology, i.e. cliques, to uncover novel pathways to accelerate our understanding of potential biological processes.

Bioinformatics Approaches for Disulfide Connectivity Prediction

Protein structure prediction with computational methods has gained much attention in the research fields of protein engineering and protein folding studies. Due to the vastness of conformational space, one of the major tasks is to restrain the flexibility of protein structure and reduce the search space. Many studies have revealed that, with the information of disulfide connectivity available, the search in conformational space can be dramatically reduced and lead to significant improvements in the prediction accuracy. As a result, predicting disulfide connectivity using bioinformatics approaches is of great interest nowadays. In this mini-review, the prediction of disulfide connectivity in proteins will be discussed in four aspects: (1) how the problem formulated and the computational techniques used in the literatures; (2) the effects of the features adopted to encode the information and the biological meanings implied; (3) the problems encountered and limitations of disulfide connectivity prediction; and (4) the practical usages of predicted disulfide bond information in molecular simulation and the prospects in the future.

A genetic algorithm for resident physician scheduling problem

This paper formally presents the resident physician scheduling problem, which is one of the most important scheduling problems in hospital. The resident physician scheduling problem is characterized as satisfying the fair schedule constraint, the physician specification constraint and the safe schedule constraint simultaneously. To minimize the penalties from violating the constraints, this study adopts the evolutionary approach to propose a genetic algorithm for solving the problems. In addition the well-known genetic operators, this study proposed a new mutation operator called dynamic mutation for solving the resident physician scheduling problem. The experimental results show that the proposed algorithm performs well in searching optimal schedules.

Improving EAX with restricted 2-opt

Edge Assembly Crossover (EAX) is by far the most successful crossover operator in solving the traveling salesman problem (TSP) with Genetic Algorithms (GAs). Various improvements have been proposed for EAX in GA. However, some of the improvements have to make compromises between performance and solution quality. In this work, we have combined several improvements proposed in the past, including heterogeneous pair selection (HpS), iterative child generation (ICG), and 2-opt. We also incorporate 2-opt into EAX, and restricted the 2-opt local searches to sub-tours in the intermediates generated by EAX.Our proposed method can improve the performance of EAX with decreased number of generations, error rates, and computation time. The applications of conventional 2-opt and our restricted 2-opt concurrently have additive effect on the performance gain, and this performance improvement is more obvious in larger problems. The proposed method also enhanced the solution quality of EAX. The significances of the restricted 2-opt and the conventional 2-opt in EAX were analyzed and discussed.

The Prediction and Analysis of Inter- and Intra-Species Protein-Protein Interaction

Protein-protein interactions (PPIs) are essential to cellular processes. Recent developments of high-throughput technologies have uncovered vast numbers of PPIs. However, the experimental evidences are mostly for intra-species interactions of model organisms, especially human. Studies of non-human organisms and inter-species PPIs are few. For organisms such as Arabidopsis thaliana, the experimentally detected 5990 PPIs are estimated to be less than 3% of the entire A. thaliana interactome (M. Lin et al., 2011). The accuracy of high-throughput PPI experiments is also doubtful (Mrowka et al., 2001; Sprinzak et al., 2003; von Mering et al., 2002). To resolve the above issues, several computational methods have been developed to evaluate and predict PPIs. This chapter focuses on direct PPIs which involve physical interactions of proteins, provides a brief overview of the reliabilities of high-throughput PPI detection technologies, and discusses the weakness and strength of important PPI computational prediction and evaluation methods. The major repositories which store, evaluate, and analyse both detected and predicted PPIs are also introduced.