Structure-Based Multiscale Approach for Identification of Interaction Partners of PDZ Domains

Tiwari, Garima; Mohanty, Debasisa

doi:10.1021/ci400627y

Cited by 8 publications

(8 citation statements)

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“…Author’s response: Our approach is based on the assumption that backbone structural variations both in the PDZ domains and the bound peptides are minimal. Analysis of crystal structures of PDZ domains and PDZ-peptide complexes in earlier studies from our group as well as others [ 11 , 14 ] have revealed that, backbone RMSDs of PDZ domains show good correlation with sequence similarities. It has also been shown that backbones of bound peptides superpose well when corresponding PDZ domains are superimposed.…”

Section: Reviewers’ Commentsmentioning

confidence: 54%

“…Therefore, it has been suggested that while MJ matrix gives more weightage to hydrophobic interactions, BT matrix can also represent hydrophilic interactions more accurately [ 19 ]. In our earlier study BT matrix was found superior to MJ matrix in identification of interaction partners of MHCs, kinases and mouse PDZ domains [ 11 , 20 – 22 ]. Therefore, we preferred to use BT pair potential [ 15 ] for scoring PDZ-peptide complexes in modPDZpep.…”

Section: Resultsmentioning

confidence: 99%

“…Secondly POW server does not provide any tool for structural analysis of binding interface, even if it uses a structure based approach for prediction of PDZ substrates. In a recent work from our group, we demonstrated that structure based approach in combination with residue based statistical pair potentials is a practical approach for genome wide scan of PDZ interaction partners and prediction accuracy of this approach was benchmarked using high throughput proteome array data on 79 mouse PDZ domains and 217 mouse proteome derived C-terminus peptides [ 8 , 11 ]. In this work, we have developed modPDZpep web server to predict the interaction partners of human PDZ domains using a structure based approach and attempted to benchmark prediction accuracy of this structure based approach using phage display and other available experimental data for human PDZ domains.…”

Section: Introductionmentioning

confidence: 99%

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modPDZpep: a web resource for structure based analysis of human PDZ-mediated interaction networks

Sain

Mohanty

2016

Biol Direct

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BackgroundPDZ domains recognize short sequence stretches usually present in C-terminal of their interaction partners. Because of the involvement of PDZ domains in many important biological processes, several attempts have been made for developing bioinformatics tools for genome-wide identification of PDZ interaction networks. Currently available tools for prediction of interaction partners of PDZ domains utilize machine learning approach. Since, they have been trained using experimental substrate specificity data for specific PDZ families, their applicability is limited to PDZ families closely related to the training set. These tools also do not allow analysis of PDZ-peptide interaction interfaces.ResultsWe have used a structure based approach to develop modPDZpep, a program to predict the interaction partners of human PDZ domains and analyze structural details of PDZ interaction interfaces. modPDZpep predicts interaction partners by using structural models of PDZ-peptide complexes and evaluating binding energy scores using residue based statistical pair potentials. Since, it does not require training using experimental data on peptide binding affinity, it can predict substrates for diverse PDZ families. Because of the use of simple scoring function for binding energy, it is also fast enough for genome scale structure based analysis of PDZ interaction networks. Benchmarking using artificial as well as real negative datasets indicates good predictive power with ROC-AUC values in the range of 0.7 to 0.9 for a large number of human PDZ domains. Another novel feature of modPDZpep is its ability to map novel PDZ mediated interactions in human protein-protein interaction networks, either by utilizing available experimental phage display data or by structure based predictions.ConclusionsIn summary, we have developed modPDZpep, a web-server for structure based analysis of human PDZ domains. It is freely available at http://www.nii.ac.in/modPDZpep.html or http://202.54.226.235/modPDZpep.html.ReviewersThis article was reviewed by Michael Gromiha and Zoltán Gáspári.Electronic supplementary materialThe online version of this article (doi:10.1186/s13062-016-0151-4) contains supplementary material, which is available to authorized users.

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Section: Reviewers’ Commentsmentioning

confidence: 54%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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modPDZpep: a web resource for structure based analysis of human PDZ-mediated interaction networks

Sain

Mohanty

2016

Biol Direct

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“…Simulations of PDZ with peptides are usually carried out for 50–100 ns to determine key residues of the PDZ domain and their role in peptide binding . The dynamic and functional properties of the two‐domain construct PDZ3‐linker‐SH3 were obtained by analysis of the evolutionary divergence of protein motions .…”

Section: Resultsmentioning

confidence: 99%

Artificial proteins as allosteric modulators of PDZ3 and SH3 in two‐domain constructs: A computational characterization of novel chimeric proteins

et al. 2016

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Artificial multidomain proteins with enhanced structural and functional properties can be utilized in a broad spectrum of applications. The design of chimeric fusion proteins utilizing protein domains or one-domain miniproteins as building blocks is an important advancement for the creation of new biomolecules for biotechnology and medical applications. However, computational studies to describe in detail the dynamics and geometry properties of two-domain constructs made from structurally and functionally different proteins are lacking. Here, we tested an in silico design strategy using all-atom explicit solvent molecular dynamics simulations. The well-characterized PDZ3 and SH3 domains of human zonula occludens (ZO-1) (3TSZ), along with 5 artificial domains and 2 types of molecular linkers, were selected to construct chimeric two-domain molecules. The influence of the artificial domains on the structure and dynamics of the PDZ3 and SH3 domains was determined using a range of analyses. We conclude that the artificial domains can function as allosteric modulators of the PDZ3 and SH3 domains. Proteins 2016; 84:1358-1374. © 2016 Wiley Periodicals, Inc.

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“…Comparing these results and SDRs from PreDiZ, most of the SDRs we used were also found in this study ( Table 2, Table 13). Another study used molecular dynamics simulations to analyse PDZ domain-peptide complexes with known binding affinities (92).…”

Section: Using a Four-parameter-test As The Sdr Selection Strategymentioning

confidence: 99%

PreDiZ: a PDZ domain-peptide interaction prediction method

Dai¹

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PDZ domains are one of the most well studied peptide binding domains. These domains usually bind short peptides at the C-terminus of their target proteins and play a crucial role in cellular signalling processes. Computational approaches have been published to determine the interaction specificity of PDZ domains, but these prediction methods often limit their predictions on a limited subset of PDZ domains. In this research work, we developed PreDiZ, a computational method for PDZ domain-peptide interaction prediction based on the SDR approach. The SDR approach was originally created to predict specificity of protein kinases. In this work, improvements have been made to apply the SDR approach to the PDZ domains, including using a more sophisticated strategy to determine SDRs, and using both positive and negative interactions in the prediction. As a result, PreDiZ is able to work on a wide range of PDZ domains, including novel PDZ domains. In cross-validations, PreDiZ scored AUCs range from 0.82 to 0.94. In the comparison against published methods, PreDiZ showed competitive performance on making prediction to distantly related PDZ domains, but not as good as other recently published methods on mouse test set.However, the results also suggested that PreDiZ could be improved by optimising SDRs. We also conducted proteome-wide predictions on A. thaliana, C. elegans, D. rerio, M. musculus and H. sapiens and showed PDZ domains were evolved relatively late in eukaryotic cells. Network studies on human PDZ domain interaction revealed the enriched GO terms and KEGG pathways of PDZ domain binding proteins. Lastly, we studied how H7N9's NA and H5N1's NS1 protein regulate human biological processes using the human PDZ interaction network. Human proteins that regulated via PDZ domain interactions by these two kind of viral proteins, were enriched in similar biological processes. Therefore, we concluded that the function of PBM in the NS1 proteins of H5N1 was replaced by the PBM in the NA proteins of H7N9.

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Structure-Based Multiscale Approach for Identification of Interaction Partners of PDZ Domains

Cited by 8 publications

References 46 publications

modPDZpep: a web resource for structure based analysis of human PDZ-mediated interaction networks

modPDZpep: a web resource for structure based analysis of human PDZ-mediated interaction networks

Artificial proteins as allosteric modulators of PDZ3 and SH3 in two‐domain constructs: A computational characterization of novel chimeric proteins

PreDiZ: a PDZ domain-peptide interaction prediction method

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