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      SkipCPP-Pred: an improved and promising sequence-based predictor for predicting cell-penetrating peptides

      research-article
      1 , 2 , 1 , 1 ,
      BMC Genomics
      BioMed Central
      12th International Symposium on Bioinformatics Research and Applications (ISBRA 2016) (ISBRA 2016)
      5-8 June 2016
      Cell-penetrating peptide, Machine learning, Adaptive k-skip-n-gram features

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          Abstract

          Background

          Cell-penetrating peptides (CPPs) are short peptides (5–30 amino acids) that can enter almost any cell without significant damage. On account of their high delivery efficiency, CPPs are promising candidates for gene therapy and cancer treatment. Accordingly, techniques that correctly predict CPPs are anticipated to accelerate CPP applications in future therapeutics. Recently, computational methods have been reportedly successful in predicting CPPs. Unfortunately, the predictive performance of existing methods is not satisfactory and reliable so as to accurately identify CPPs.

          Results

          In this study, we propose a novel computational predictor called SkipCPP-Pred to further improve the predictive performance. The novelty of the proposed predictor is that we present a sequence-based feature representation algorithm called adaptive k-skip-n-gram that sufficiently captures the intrinsic correlation information of residues. By fusing the proposed adaptive skip features with a random forest (RF) classifier, we successfully construct the prediction model of SkipCPP-Pred. The various jackknife results demonstrate that the proposed SkipCPP-Pred is 3.6% higher than state-of-the-art CPP predictors in terms of accuracy. Moreover, we construct a high-quality benchmark dataset by reducing the data redundancy and enhancing the similarity between the positive and negative classes. Using this dataset to build prediction models, we can successfully avoid the performance bias lying in existing methods and yield a promising predictive model.

          Conclusions

          The proposed SkipCPP-Pred is a simple and fast sequence-based predictor featured with the adaptive k-skip-n-gram model for the improved prediction of CPPs. Currently, SkipCPP-Pred is publicly available from an online webserver ( http://server.malab.cn/SkipCPP-Pred/Index.html).

          Electronic supplementary material

          The online version of this article (10.1186/s12864-017-4128-1) contains supplementary material, which is available to authorized users.

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          Most cited references59

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          The meaning and use of the area under a receiver operating characteristic (ROC) curve.

          A representation and interpretation of the area under a receiver operating characteristic (ROC) curve obtained by the "rating" method, or by mathematical predictions based on patient characteristics, is presented. It is shown that in such a setting the area represents the probability that a randomly chosen diseased subject is (correctly) rated or ranked with greater suspicion than a randomly chosen non-diseased subject. Moreover, this probability of a correct ranking is the same quantity that is estimated by the already well-studied nonparametric Wilcoxon statistic. These two relationships are exploited to (a) provide rapid closed-form expressions for the approximate magnitude of the sampling variability, i.e., standard error that one uses to accompany the area under a smoothed ROC curve, (b) guide in determining the size of the sample required to provide a sufficiently reliable estimate of this area, and (c) determine how large sample sizes should be to ensure that one can statistically detect differences in the accuracy of diagnostic techniques.
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            Arginine-rich peptides. An abundant source of membrane-permeable peptides having potential as carriers for intracellular protein delivery.

            A basic peptide derived from human immunodeficiency virus (HIV)-1 Tat protein (positions 48-60) has been reported to have the ability to translocate through the cell membranes and accumulate in the nucleus, the characteristics of which are utilized for the delivery of exogenous proteins into cells. Based on the fluorescence microscopic observations of mouse macrophage RAW264.7 cells, we found that various arginine-rich peptides have a translocation activity very similar to Tat-(48-60). These included such peptides as the d-amino acid- and arginine-substituted Tat-(48-60), the RNA-binding peptides derived from virus proteins, such as HIV-1 Rev, and flock house virus coat proteins, and the DNA binding segments of leucine zipper proteins, such as cancer-related proteins c-Fos and c-Jun, and the yeast transcription factor GCN4. These segments have no specific primary and secondary structures in common except that they have several arginine residues in the sequences. Moreover, these peptides were able to be internalized even at 4 degrees C. These results strongly suggested the possible existence of a common internalization mechanism ubiquitous to arginine-rich peptides, which is not explained by a typical endocytosis. Using (Arg)(n) (n = 4-16) peptides, we also demonstrated that there would be an optimal number of arginine residues (n approximately 8) for the efficient translocation.
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              Mechanisms of Cellular Uptake of Cell-Penetrating Peptides

              Recently, much attention has been given to the problem of drug delivery through the cell-membrane in order to treat and manage several diseases. The discovery of cell penetrating peptides (CPPs) represents a major breakthrough for the transport of large-cargo molecules that may be useful in clinical applications. CPPs are rich in basic amino acids such as arginine and lysine and are able to translocate over membranes and gain access to the cell interior. They can deliver large-cargo molecules, such as oligonucleotides, into cells. Endocytosis and direct penetration have been suggested as the two major uptake mechanisms, a subject still under debate. Unresolved questions include the detailed molecular uptake mechanism(s), reasons for cell toxicity, and the delivery efficiency of CPPs for different cargoes. Here, we give a review focused on uptake mechanisms used by CPPs for membrane translocation and certain experimental factors that affect the mechanism(s).
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                Author and article information

                Contributors
                weileyi@tju.edu.cn
                JTANG@cse.sc.edu
                zouquan@nclab.net
                Conference
                BMC Genomics
                BMC Genomics
                BMC Genomics
                BioMed Central (London )
                1471-2164
                16 October 2017
                16 October 2017
                2017
                : 18
                Issue : Suppl 7 Issue sponsor : Publication of this supplement has not been supported by sponsorship. Information about the source of funding for publication charges can be found in the individual articles. The articles have undergone the journal's standard peer review process for supplements. The Supplement Editors declare that they have no competing interests.
                : 1-11
                Affiliations
                [1 ]ISNI 0000 0004 1761 2484, GRID grid.33763.32, School of Computer Science and Technology, Tianjin University, ; Tianjin, 30050 China
                [2 ]ISNI 0000 0000 9878 7032, GRID grid.216938.7, State Key Laboratory of Medicinal Chemical Biology, , Nankai University, ; Tianjin, 300074 China
                Article
                4128
                10.1186/s12864-017-4128-1
                5657092
                29513192
                2bed4a32-c413-4d7b-b742-9f4d2a4fc8b6
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                12th International Symposium on Bioinformatics Research and Applications (ISBRA 2016)
                ISBRA 2016
                Minsk, Belarus
                5-8 June 2016
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                © The Author(s) 2017

                Genetics
                cell-penetrating peptide,machine learning,adaptive k-skip-n-gram features
                Genetics
                cell-penetrating peptide, machine learning, adaptive k-skip-n-gram features

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