Details of a Researcher - Tomita, Masaru

Papers - Tomita, Masaru

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Cancer metabolomics: Toward the development of novel anticancer therapeutics targeting the energy metabolism in tumor microenvironment

Kami K., Tomitsuka E., Kita K., Tomita M., Soga T., Esumi H.

Japanese Journal of Clinical Chemistry 37 ( 4 ) 361 - 367 2008.12

ISSN 03705633

Role of Na<sup>+</sup>-Ca<sup>2+</sup> exchange in neonatal and adult ventricular cells

Sano H., Naito Y., Tomita M.

WMSCI 2008 - The 12th World Multi-Conference on Systemics, Cybernetics and Informatics, Jointly with the 14th International Conference on Information Systems Analysis and Synthesis, ISAS 2008 - Proc. 2 142 - 144 2008.12

The present paper expanded an integrated mathematical model, which successfully simulated developmental changes in electrophysiological activities of rodent ventricular cells, to contrive models that reflect one of the hypothesis on the role of Na+-Ca"+ exchange in neonatal ventricular cell: the Na+-Ca+ exchange assumes a relatively greater role in neonatal cells with a morphologically sparse SR. Our simulation with the expanded model showed that neonatal ventricular cell consumed larger amount of adenosine triphosphate (ATP) than adult ventricular cell did, owing to long relaxation time. The amount of ATP consumed per beat was reduced to the amount equivalent to adult ventricular cell, as increasing the relative current density of Na+-Ca2+ exchange (F NCx) by 4-fold, which is consistent with the observed current density in neonatal rabbit ventricular cell. To further validate the hypothesis, the relative functional activity of SR (FSR) was incrementally increased from neonatal to adult levels and subsequently increased FNCX, and found that increasing FNcx had negative impact on sarcomere relaxation velocity in ventricular cell model with large FSR. All the results thus theoretically supported the hypothesis that the Na+-Ca2+ exchange assumes a relatively greater role in neonatal cells with a morphologically sparse SR.

Signaling flux redistribution at toll-like receptor pathway junctions

Selvarajoo K., Takada Y., Gohda J., Helmy M., Akira S., Tomita M., Tsuchiya M., Inoue J.I., Matsuo K.

PLoS ONE 3 ( 10 ) e3430 2008.10

Various receptors on cell surface recognize specific extracellular molecules and trigger signal transduction altering gene expression in the nucleus, Gain or loss-of-function mutations of one molecule have shown to affect alternative signaling pathways with a poorly understood mechanism. In Toll-like receptor (TLR) 4 signaling, which branches into MyD88- and TRAM-dependent pathways upon lipopolysaccharide (LPS) stimulation, we investigated the gain or loss-of-function mutations of MyD88. We predict, using a computational model built on the perturbation-response approach and the law of mass conservation, that removal and addition of MyD88 in TLR4 activation, enhances and impairs, respectively, the alternative TRAM-dependent pathway through signaling flux redistribution (SFR) at pathway branches. To verify SFR, we treated MyD88-deficient macrophages with LPS and observed enhancement of TRAM-dependent pathway based on increased IRF3 phosphorylation and induction of Cxcl10 and lfit2. Furthermore, increasing the amount of MyD88 in cultured cells showed decreased TRAM binding to TLR4. Investigating another TLR4 pathway junction, from TRIF to TRAF6, RIP1 and TBK1, the removal of MyD88-dependent TRAF6 increased expression of TRAM-dependent Cxl10 and lfit2. Thus, we demonstrate that SFR is a novel mechanism for enhanced activation of alternative pathways when molecules at pathway junctions are removed. Our data suggest that SFR may enlighten hitherto unexplainable intracellular signaling alterations in genetic diseases where gain or loss-of-function mutations are observed. © 2008 Selvarajoo et al.

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Design of Peptide Inhibitors for the Importin α/β Nuclear Import Pathway by Activity-Based Profiling

Kosugi S., Hasebe M., Entani T., Takayama S., Tomita M., Yanagawa H.

Chemistry and Biology 15 ( 9 ) 940 - 949 2008.09

ISSN 10745521

Despite the current availability of selective inhibitors for the classical nuclear export pathway, no inhibitor for the classical nuclear import pathway has been developed. Here we describe the development of specific inhibitors for the importin α/β pathway using a novel method of peptide inhibitor design. An activity-based profile was created via systematic mutational analysis of a peptide template of a nuclear localization signal. An additivity-based design using the activity-based profile generated two peptides with affinities for importin α that were approximately 5 million times higher than that of the starting template sequence. The high affinity of these peptides resulted in specific inhibition of the importin α/β pathway. These peptide inhibitors provide a useful tool for studying nuclear import events. Moreover, our inhibitor design method should enable the development of potent inhibitors from a peptide seed. © 2008 Elsevier Ltd. All rights reserved.

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Stabilizing synthetic data in the DNA of living organisms

Yachie N, Ohashi Y, Tomita M

Syst Synth Biol. 2 ( 1-2 ) 19-25 - 25 2008.06

Research paper (scientific journal), Joint Work, ISSN 18725325

Data-encoding synthetic DNA, inserted into the genome of a living organism, is thought to be more robust than the current media. Because the living genome is duplicated and copied into new generations, one of the merits of using DNA material is long-term data storage within heritable media. A disadvantage of this approach is that encoded data can be unexpectedly broken by mutation, deletion, and insertion of DNA, which occurs naturally during evolution and prolongation, or laboratory experiments. For this reason, several information theory-based approaches have been developed as an error check of broken DNA data in order to achieve data durability. These approaches cannot efficiently recover badly damaged data- encoding DNA. We recently developed a DNA data-storage approach based on the multiple sequence alignment method to achieve a high level of data durability. In this paper, we overview this technology and discuss strategies for optimal application of this approach.

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GANDivAWeb: A web server for detecting early folding units ("foldons") from protein 3D structures

Laborde T., Tomita M., Krishnan A.

BMC Structural Biology 8 2008.05

Background. It has long been known that small regions of proteins tend to fold independently and are then stabilized by interactions between these distinct subunits or modules. Such units, also known as autonomous folding units (AFUs) or"foldons" play a key role in protein folding. A knowledge of such early folding units has diverse applications in protein engineering as well as in developing an understanding of the protein folding process. Such AFUs can also be used as model systems in order to study the structural organization of proteins. Results. In an earlier work, we had utilized a global network partitioning algorithm to identify modules in proteins. We had shown that these modules correlate well with AFUs. In this work, we have developed a webserver, GANDivAWeb, to identify early folding units or "foldons" in networks using the algorithm described earlier. The website has three functionalities: (a) It is able to display information on the modularity of a database of 1420 proteins used in the original work, (b) It can take as input an uploaded PDB file, identify the modules using the GANDivA algorithm and email the results back to the user and (c) It can take as input an uploaded PDB file and a results file (obtained from functionality (b)) and display the results using the embedded viewer. The results include the module decomposition of the protein, plots of cartoon representations of the protein colored by module identity and connectivity as well as contour plots of the hydrophobicity and relative accessible surface area (RASA) distributions. Conclusion. We believe that the GANDivAWeb server, will be a useful tool for scientists interested in the phenomena of protein folding as well as in protein engineering. Our tool not only provides a knowledge of the AFUs through a natural graph partitioning approach but is also able to identify residues that are critical during folding. It is our intention to use this tool to study the topological determinants of protein folding by analyzing the topological changes in proteins over the unfolding/folding pathways. © 2008 Laborde et al; licensee BioMed Central Ltd.

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Large-scale phosphorylation mapping reveals the extent of tyrosine phosphorylation in Arabidopsis

Sugiyama,N., Nakagami,H., Mochida,K., Daudi,A., Tomita,M., Shirasu,K., and Ishihama,Y.

Mol Syst Biol. 4 193 2008.05

Research paper (scientific journal), Joint Work, ISSN 17444292

Protein phosphorylation regulates a wide range of cellular processes. Here, we report the proteome-wide mapping of in vivo phosphorylation sites in Arabidopsis by using complementary phosphopeptide enrichment techniques coupled with high-accuracy mass spectrometry. Using unfractionated whole cell lysates of Arabidopsis, we identified 2597 phosphopeptides with 2172 high-confidence, unique phosphorylation sites from 1346 proteins. The distribution of phosphoserine, phosphothreonine, and phosphotyrosine sites was 85.0, 10.7, and 4.3%. Although typical tyrosine-specific protein kinases are absent in Arabidopsis, the proportion of phosphotyrosines among the phospho-residues in Arabidopsis is similar to that in humans, where over 90 tyrosine-specific protein kinases have been identified. In addition, the tyrosine phosphoproteome shows features distinct from those of the serine and threonine phosphoproteomes. Taken together, we highlight the extent and contribution of tyrosine phosphorylation in plants. © 2008 EMBO and Nature Publishing Group.

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Developing Bottom-fermenting Yeast Strains That Produce High SO2 Levels by Integrated Metabolome and Transcriptome Analysis

Yoshida S., Imoto J., Minato T., Oouchi R., Sugihara M., Imai T., Ishiguro T., Mizutani S., Tomita M., Soga T., Yoshimoto H.

Applied and Environmental Microbiology 74 ( 9 ) 2787 - 2796 2008.05

ISSN 00992240

Sulfite plays an important role in beer flavor stability. Although breeding of bottom-fermenting Saccharomyces strains that produce high levels of SO 2 is desirable, it is complicated by the fact that undesirable H 2S is produced as an intermediate in the same pathway. Here, we report the development of a high-level SO2-producing bottom-fermenting yeast strain by integrated metabolome and transcriptome analysis. This analysis revealed that O-acetylhomoserine (OAH) is the rate-limiting factor for the production of SO2 and H2S. Appropriate genetic modifications were then introduced into a prototype strain to increase metabolic fluxes from aspartate to OAH and from sulfate to SO 2, resulting in high SO2 and low H2S production. Spontaneous mutants of an industrial strain that were resistant to both methionine and threonine analogs were then analyzed for similar metabolic fluxes. One promising mutant produced much higher levels of SO2 than the parent but produced parental levels of H2S. Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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Phase transfer surfactant-aided trypsin digestion for membrane proteome analysis

Masuda T., Tomita M., Ishihama Y.

Journal of Proteome Research 7 ( 2 ) 731 - 740 2008.02

ISSN 15353893

We have developed a new protocol for digesting hydrophobic proteins using trypsin with the aid of phase-transfer surfactants (PTS), such as sodium deoxycholate (SDC). SDC increases the solubility of hydrophobic proteins, enhances the activity of trypsin, and improves the accessibility to trypsin of proteins denatured during the extraction process. After digestion, SDC was successfully removed from the acidified solution containing tryptic peptides by adding a water-immiscible organic solvent, into which SDC was predominantly transferred, while the digested peptides remained in the aqueous phase. Compared with a protocol using an acid-labile surfactant, this PTS protocol increased the number of identified proteins and the recovery of hydrophobic peptides in the analysis of 400 ng of a membrane-enriched fraction of Escherichia coli. Application of the PTS protocol to 9.0 μg of a membrane-enriched pellet from human cervical cancer HeLa cells resulted in identification of a total of 1450 proteins, of which 764 (53%) were membrane proteins, by two-dimensional strong cation exchange (SCX)-C18 LC-MSMS with 5 SCX fractions. The distribution of the number of transmembrane domains in proteins identified in this study was in agreement with that in the IPI human database, suggesting that the PTS protocol can provide unbiased digestion of the membrane proteome. © 2008 American Chemical Society.

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Perspective in the evolution of human microRNAs: Copy number expansion and acquisition of target gene specialization

Watanabe Y., Tomita M., Kanai A.

Progress of Theoretical Physics Supplement ( 173 ) 219 - 228 2008

ISSN 03759687

A novel class of small, noncoding RNAs called microRNAs (miRNAs) was recently identified, and up to 20%-30% of human genes are said to be regulated by the members of this class of RNA. miRNAs regulate their target genes by imperfect binding to the 3′ untranslated region (UTR) of the gene transcript, and computational predictions of the binding between miRNAs and target gene transcripts have been performed in order to determine which genes are regulated by these RNAs. Phylogenetic analysis has also been used as a powerful tool to predict miRNA target genes. Much emphasis has therefore been placed on studying the phylogenetic conservation and evolution of this novel type of gene regulator, although there still is much that is not known. Here, we propose a hypothesis of how human miRNAs optimized their gene regulation by adjusting their transcript levels, and how they evolved through specific selection of their target genes. We analyzed the correlation between the conservation of miRNAs among species and three features: the number of transcripts, the formation of duplicates, and the number of target genes. The number of miRNA transcripts and the formation of duplicates increased as the conservation rate increased. In contrast, the number of target genes decreased as the conservation rate increased. Therefore, we propose that miRNAs gradually gain an ability to regulate specific target genes when such regulation has a positive effect on the organism. As its pool of target genes is refined, the ability of an miRNA to regulate the genes may be stabilized by an increase in the miRNA transcript number and the formation of duplicates.

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Nuclear export signal consensus sequences defined using a localization-based yeast selection system

Kosugi, S., Hasebe, M., Tomita, M. and Yanagawa, H.

Traffic 9 ( 12 ) 2053 - 2062 2008

Joint Work, ISSN 13989219

Proteins bearing nuclear export signals (NESs) are translocated to the cytoplasm from the nucleus mainly through the CRM1-dependent pathway. However, the NES consensus sequence remains poorly defined, and there are currently no high-throughput methods for identifying NESs. In this study, we report the development of an efficient yeast selection system for detecting nuclear export activity as well as several reliable NES consensus sequences identified using this method. Our selection system is based on the nuclear export-dependent rescue of Tys1p, an essential cytoplasmic protein that has been artificially localized to the nucleus in a haploid Δtys1 knockout strain. A screen of a random peptide library revealed 101 distinct CRM1-dependent NESs, which were classified into six patterns according to the conserved hydrophobic spacing. By combining mutational analyses, we have defined new NES consensus sequences with more specific and redundant residues than the traditional consensus sequence, which are consistent with most experimentally confirmed NESs. These NES consensus sequences should help identify functional NESs, and our selection system can be used to identify other targeting signals or proteins imported to specific subcellular compartments. © 2008 The Authors Journal compilation © 2008 Blackwell Munksgaard.

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Comparison and characterization of proteomes in the three domains of life using 2D correlation analysis

Fujishima K., Komasa M., Kitamura S., Tomita M., Kanai A.

Progress of Theoretical Physics Supplement ( 173 ) 206 - 218 2008

ISSN 03759687

Proteins are a major regulatory component in complex biological systems. Among them, DNA/RNA-binding proteins, the key components of the central dogma of molecular biology, and membrane proteins, which are necessary for both signal transduction and metabolite transport, are suggested to be the most important protein families that arose in the early stage of life. In this study, we computationally analyzed the whole proteome data of six model species to overview the protein diversity in the three domains of life (Bacteria, Archaea and Eukaryota), especially focusing on the above two protein families. To compare the protein distribution among the six model species, we calculated various protein profiles: hydropathy, molecular weight, amino acid composition and periodicity for each protein. We found a domain-specific distribution of the proteome based on 2D correlation analysis of hydropathy and molecular weight. Further, the merged protein distribution of Archaea and other domains revealed many membrane proteins localized in Bacteria-specific regions with a high ratio of hydropathy and many DNA/RNA-binding proteins localized in Eukaryota-specific regions with a low ratio of hydropathy. Since about half of the proteins encoded in the genome are still functionally unknown, we further conducted Support Vector Machine (SVM)-based functional prediction using amino acid composition (CO score) and periodicity (PD score) as feature vectors to predict the overall number of DNA/RNA-binding proteins and membrane proteins in the proteome. Our estimation indicated that two functional categories occupy approximately 60% to 80% of the proteome, and further, the proportion of the two categories varied among the three domains of life, suggesting that the proteome has gone through different selective pressure during evolution.

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Construction of a Biological Tissue Model Based on a Single-Cell Model: A Computer Simulation of Metabolic Heterogeneity in the Liver Lobule

Ohno, H., Naito, Y., Nakajima, H. and Tomita, M.

Artificial Life 14 ( 1 ) 3-28 - 28 2008

Research paper (scientific journal), Joint Work, ISSN 10645462

An enormous body of information has been obtained by molecular and cellular biology in the last half century, However, even these powerful approaches are not adequate when it comes to higher-level biological structures, such as tissues, organs, and individual organisms, because of the complexities involved. Thus, accumulation of data at the higher levels supports and broadens the context for that obtained on the molecular and cellular levels. Under such auspices, an attempt to clucidate mesoscopic and macroscopic subjects based on plentiful nanoscopic and microscopic data is ot great potential value. On the other hand, fully realistic simulation is impracticable because of the extensive cost entailed and enormous amount of data required. Abstraction and modeling that balance the dual requirements of prediction accuracy and manageable calculation cost are of great importance for systems biology. We have constructed an ammonia metabolism model of the hepatic lobule, a histological component of the liver, based on a single-hepatocyte model that consists of the biochemical kinetics of enzymes and transporters. To bring the calculation cost within reason, the porto-central axis, which is an elemental structure of the lobule, is defined as the systems biological unit of the liver, and is accordingly modeled. A model including both histological structure and position-specific gene expression of major enzymes largely represents the physiological dynamics of the hepatic lobule in nature. In addition, heterogeneous gene expression is suggested to have evolved to optimize the energy efficiency of ammonia detoxificattion at the macroscopic level, implying that approaches like this may elucidate how properties at the molecular and cellular levels, such as regulated gene expression, modify higher-level phenomena of multicellular tissue, organs, and organisms. © 2008 Massachusetts Institute of Technology.

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Comparative Study of Circadian Oscillatory Network Models of Drosophila

Ogawa, Y., Arakawa, K., Kaizu, K., Miyoshi, F., Nakayama, Y. and Tomita, M.

Artificial Life 14 ( 1 ) 29-48 - 48 2008

Research paper (scientific journal), Joint Work, ISSN 10645462

The circadian clock of Drosophila is a model pathway for research in biological dock mechanisms, both with traditional experimental approaches and with emerging systems biology approaches utilizing mathematical modeling and in silico computer simulation. Dynamic diurnal oscillations are achieved by the complex interaction of components as a system, and mathematical reconstruction his proven to be an invaluable means of understanding such systematic behavior. In this study, we implemented eight published models of the Drosqpbila circadian clock in Systems Biology Markup Language (SBML) for comparative systems biology studies using E-Cell Simulation Environment version 3, to examine the system-level requirements for the clock mechanism to be robust, by calculating the period and amplitude sensitivity coefficients with simulation experiments. While all models were generally robust as determined by the network topology of the oscillatory feedback loop structure, existing models place relatively strong emphasis on transcription regulation, although this is a limitation on robustness. We suggest that more comprehensive modeling including protein phosphorylation, polymerization, and nuclear transport with regard to amplitude sensitivity will be necessary for understanding the light entrainment and temperature compensation of circadian clocks. © 2008 Massachusetts Institute of Technology.

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Algebraic Method for the Analysis of Signaling Crosstalk

Matsubara, Y., Kikuchi, S., Sugimoto, M., Oka, K. and Tomita, M.

Artificial Life 14 ( 1 ) 81-94 - 94 2008

Research paper (scientific journal), Joint Work, ISSN 10645462

A unified mathematical description that expresses the characteristics of whole systems is necessary for an understanding of signal transduction cascades. In this study we explore an algebraic method, named extreme signaling flow, enhanced from the concept of extreme pathway, to analyze signal transduction systems. This method enables us to represent the long-term potentiation (LTP) and the long-term depression (LTD) of hippocampal neuronal plasticity in an integrated simulation model. The model is validated by comparing the results of redundancy, reaction participation, and in silico knockout analysis with biological knowledge available from the literature. The following properties are assumed in these computational analyses: (1) LTP is fault-tolerant under network modification, (2) protein kinase C and MAPK have numerous routes to LTP induction, (3) calcium-calmodulin kinase II has a few routes to LTP induction, and (4) calcineurin has many routes to LTD induction. These results demonstrate that our approach produces an integrated framework for analyzing properties of large-scale systems with complicated signal transduction. © 2008 Massachusetts Institute of Technology.

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Automated Phosphoproteome Analysis for Cultured Cancer Cells by Two-Dimensional NanoLC-MS Using a Calcined Titania/C18 Biphasic Column

Imami, K., Sugiyama, N., Kyono, Y., Tomita, M. and Ishihama, Y.

Innovations in Analytical Sciences 24 ( 1 ) 161 - 166 2008

Research paper (scientific journal), Joint Work, ISSN 09106340

We have developed an on-line automated system for phosphoproteome analysis using titania-based phosphopeptide enrichment followed by nanoLC-MS/MS. Titania beads were prepared by calcination of commercial chromatographic titania beads at 800°C to convert the crystalline structure. The obtained rutile-form titania exhibited higher selectivity in phosphopeptide enrichment than commercial titania, even in the absence of a competitive chelating reagent for non-phosphopeptides. For phosphoproteome analysis of human cervical cancer HeLa cells, tryptic digests of the cell extracts were directly injected into this on-line system, and 696 non-redundant phosphopeptides with 671 unambiguously determined phosphorylation sites, derived from 512 phosphoproteins, were successfully identified. This is the first successful application of an on-line automated phosphoproteome analysis system to complex biological samples. 2008 © The Japan Society for Analytical Chemistry.

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Depiction of metabolome changes in histidine-starved Escherichia coli by CE-TOFMS

Ohashi,Y.,Hirayama,A.,Ishikawa,T.,Nakamura,S.,Shimizu,K.,Ueno,Y.,Tomita,M.and Soga,T.

Mol.BioSyst 4 ( 2 ) 135-147 - 147 2008

Research paper (scientific journal), Joint Work, ISSN 1742206X

Metabolic changes in response to histidine starvation were observed in histidine-auxotrophic Escherichia coli using a capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS)-based metabolomics technique. Prior to the analysis, we prepared an E. coli metabolome list of 727 metabolites reported in the literature. An improved method for metabolite extraction was developed, which resulted in higher extraction efficiency in phosphate-rich metabolites, e.g., ATP and GTP. Based on the results, 375 charged, hydrophilic intermediates in primary metabolisms were analysed simultaneously, providing quantitative data of 198 metabolites. We confirmed that the intracellular levels of intermediates in histidine biosynthesis are rapidly accumulated in response to a drop in histidine level under histidine-starved conditions. Simultaneously, disciplined responses were observed in the glycolysis, tricarboxylic acid cycle, and amino acid and nucleotide biosynthesis pathways as regulated by amino acid starvation. © The Royal Society of Chemistry.

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Evolution of gene regulatory networks:Robustness as an emergent property of evolution

Krishnan,A.,Tomita,M.and Giuliani,A.

Physica A:Statistical Mechanics nad its Applications 387 ( 8-9 ) 2170-2186 - 2186 2008

Research paper (scientific journal), Joint Work, ISSN 03784371

Gene Regulatory Networks (GRNs) have become a major focus of interest in recent years. Although much work has been done in elucidating the transcriptional regulatory network, the underlying mechanisms that have possibly influenced the evolution of these GRNs are still debatable. We have developed a framework to analyze the effect of objective functions, input types and starting populations on the evolution of GRNs with a specific emphasis on the robustness of evolved GRNs. We observed that robustness evolves along with the networks as an emergent property even in the absence of specific selective pressure towards more robust systems. In addition, robustness was independent of the selective pressure, input types or the initial starting populations. We also observed the existence of multiple genotypes giving rise to the same phenotype in accordance with the theoretical view that natural selection operates on phenotypes thereby accommodating variation in the genotype by fixing those changes that are phenotype-neutral. This study gives a proof-of-concept of the fact that robustness is an emergent property of GRNs as well as of the degeneracy of the network topology/function relationship analogous to the sequence/structure problem in proteins. © 2007 Elsevier Ltd. All rights reserved.

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Reshuffling of the Bacillus subtilis 168 genome by multifold inversion

Kuroki,A.,TOda,T.,Matsui,K.,Uotsu-Tomita,R.,Tomita,M.and Itaya,M.

Journal of Biochemistry 143 ( 1 ) 97-105 - 105 2008

Research paper (scientific journal), Joint Work, ISSN 0021924X

The genome of Bacillus subtilis 168 was modified to yield a genome vector for the cloning of DNA several Mb in size. Unlike contemporary plasmid-based vectors, this 4.2 Mb genome vector requires specific in vivo handling protocols because of its large size. Inversion mutagenesis, a method to modify local genome structure without gain or loss of genes, was applied intensively to the B. subtilis genome; this technique made possible both exchange and translocation of designated regions of the genome. This method not only reshuffles the genome of B. subtilis, but can provide insight into the biologic principles underlying genome plasticity. © 2007 The Japanese Biochemical Society.

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Informatics for Peptide Retention Properties in Proteomic LC-MS

Shinoda, K., Sugimoto, M., Tomita, M. and Ishihama, Y.

Proteomics 8 ( 4 ) 787-98 - 798 2008

Research paper (scientific journal), Joint Work, ISSN 16159853

Retention times in HPLC yield valuable information for the identification of various analytes and the prediction of peptide retention is useful for the identification of peptides/proteins in LC-MS-based proteomics. Informatics methods such as artificial neural networks and support vector machines capable of solving nonlinear problems made possible the accurate modeling of quantitative structure-retention relationships of peptides (including large polymers) up to 5 kDa to which classical linear models cannot be applied, as well as the proteome-wide prediction of peptide retention. Proteome-wide retention prediction and accurate mass-information facilitate the identification of peptides in complex proteomic samples. In this review, we address recent developments in solid informatics methods and their application to peptide-retention properties in 'bottom-up' shotgun proteomics. We also describe future prospects for the standardization and application of retention times. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA.

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