TMBpro: secondary structure, beta-contact and tertiary structure prediction of transmembrane beta-barrel proteins

MOTIVATION Transmembrane beta-barrel (TMB) proteins are embedded in the outer membranes of mitochondria, Gram-negative bacteria and chloroplasts. These proteins perform critical functions, including active ion-transport and passive nutrient intake. Therefore, there is a need for accurate prediction of secondary and tertiary structure of TMB proteins. Traditional homology modeling methods, however, fail on most TMB proteins since very few non-homologous TMB structures have been determined. Yet, because TMB structures conform to specific construction rules that restrict the conformational space drastically, it should be possible for methods that do not depend on target-template homology to be applied successfully. RESULTS We develop a suite (TMBpro) of specialized predictors for predicting secondary structure (TMBpro-SS), beta-contacts (TMBpro-CON) and tertiary structure (TMBpro-3D) of transmembrane beta-barrel proteins. We compare our results to the recent state-of-the-art predictors transFold and PRED-TMBB using their respective benchmark datasets, and leave-one-out cross-validation. Using the transFold dataset TMBpro predicts secondary structure with per-residue accuracy (Q(2)) of 77.8%, a correlation coefficient of 0.54, and TMBpro predicts beta-contacts with precision of 0.65 and recall of 0.67. Using the PRED-TMBB dataset, TMBpro predicts secondary structure with Q(2) of 88.3% and a correlation coefficient of 0.75. All of these performance results exceed previously published results by 4% or more. Working with the PRED-TMBB dataset, TMBpro predicts the tertiary structure of transmembrane segments with RMSD <6.0 A for 9 of 14 proteins. For 6 of 14 predictions, the RMSD is <5.0 A, with a GDT_TS score greater than 60.0. AVAILABILITY http://www.igb.uci.edu/servers/psss.html.

[1]  G. Heijne,et al.  Genome‐wide analysis of integral membrane proteins from eubacterial, archaean, and eukaryotic organisms , 1998, Protein science : a publication of the Protein Society.

[2]  Burkhard Rost,et al.  PROFtmb: a web server for predicting bacterial transmembrane beta barrel proteins , 2006, Nucleic Acids Res..

[3]  L. Tamm,et al.  Folding and assembly of β-barrel membrane proteins , 2004 .

[4]  J. Skolnick,et al.  TOUCHSTONE II: a new approach to ab initio protein structure prediction. , 2003, Biophysical journal.

[5]  William C Wimley,et al.  The versatile beta-barrel membrane protein. , 2003, Current opinion in structural biology.

[6]  Pierre Baldi,et al.  Improving the prediction of protein secondary structure in three and eight classes using recurrent neural networks and profiles , 2002, Proteins.

[7]  Benjamin J. Raphael,et al.  The Sorcerer II Global Ocean Sampling Expedition: Expanding the Universe of Protein Families , 2007, PLoS biology.

[8]  William C. Wimley,et al.  The versatile β-barrel membrane protein , 2003 .

[9]  K. Diederichs,et al.  Prediction by a Neural Network of Outer Membrane P-strand Protein Topology , 1998 .

[10]  P. van Gelder,et al.  Structure and function of bacterial outer membrane proteins: barrels in a nutshell , 2000, Molecular microbiology.

[11]  David R. Westhead,et al.  TMB-Hunt: An amino acid composition based method to screen proteomes for beta-barrel transmembrane proteins , 2005, BMC Bioinformatics.

[12]  Jie Liang,et al.  Interstrand pairing patterns in beta-barrel membrane proteins: the positive-outside rule, aromatic rescue, and strand registration prediction. , 2005, Journal of molecular biology.

[13]  Piero Fariselli,et al.  In silico prediction of the structure of membrane proteins: Is it feasible? , 2003, Briefings Bioinform..

[14]  Masami Ikeda,et al.  TMPDB: a database of experimentally-characterized transmembrane topologies , 2003, Nucleic Acids Res..

[15]  Shandar Ahmad,et al.  TMBETA-NET: discrimination and prediction of membrane spanning β-strands in outer membrane proteins , 2005, Nucleic Acids Res..

[16]  Yungok Ihm,et al.  A limited universe of membrane protein families and folds , 2006, Protein science : a publication of the Protein Society.

[17]  Krzysztof Fidelis,et al.  Processing and evaluation of predictions in CASP4 , 2001, Proteins.

[18]  Stavros J. Hamodrakas,et al.  Evaluation of methods for predicting the topology of β-barrel outer membrane proteins and a consensus prediction method , 2005, BMC Bioinformatics.

[19]  Pierre Baldi,et al.  Large‐scale prediction of disulphide bridges using kernel methods, two‐dimensional recursive neural networks, and weighted graph matching , 2005, Proteins.

[20]  Paul Horton,et al.  Discrimination of outer membrane proteins using support vector machines , 2005, Bioinform..

[21]  G. Schulz,et al.  Prediction of the general structure of OmpF and PhoE from the sequence and structure of porin from Rhodobacter capsulatus. Orientation of porin in the membrane. , 1991, Biochimica et biophysica acta.

[22]  S. Bryant,et al.  Critical assessment of methods of protein structure prediction (CASP): Round II , 1997, Proteins.

[23]  Piero Fariselli,et al.  A sequence-profile-based HMM for predicting and discriminating beta barrel membrane proteins , 2002, ISMB.

[24]  Pierre Baldi,et al.  Accurate Prediction of Protein Disordered Regions by Mining Protein Structure Data , 2005, Data Mining and Knowledge Discovery.

[25]  M. Saier,et al.  The β‐barrel finder (BBF) program, allowing identification of outer membrane β‐barrel proteins encoded within prokaryotic genomes , 2002 .

[26]  G. Schulz.  β-Barrel membrane proteins , 2000 .

[27]  W. Kabsch,et al.  Dictionary of protein secondary structure: Pattern recognition of hydrogen‐bonded and geometrical features , 1983, Biopolymers.

[28]  W. Wimley.  Toward genomic identification of β‐barrel membrane proteins: Composition and architecture of known structures , 2002, Protein science : a publication of the Protein Society.

[29]  Andrei L. Lomize,et al.  OPM: Orientations of Proteins in Membranes database , 2006, Bioinform..

[30]  Peter Clote,et al.  transFold: a web server for predicting the structure and residue contacts of transmembrane beta-barrels , 2006, Nucleic Acids Res..

[31]  Pierre Baldi,et al.  The Principled Design of Large-Scale Recursive Neural Network Architectures--DAG-RNNs and the Protein Structure Prediction Problem , 2003, J. Mach. Learn. Res..

[32]  Adam Zemla,et al.  LGA: a method for finding 3D similarities in protein structures , 2003, Nucleic Acids Res..

[33]  Henry R. Bigelow,et al.  Predicting transmembrane beta-barrels in proteomes. , 2004, Nucleic acids research.

[34]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[35]  Qi Liu,et al.  A HMM-based method to predict the transmembrane regions of \beta-barrel membrane proteins , 2003, Comput. Biol. Chem..

[36]  R. Casadio,et al.  Prediction of the transmembrane regions of β‐barrel membrane proteins with a neural network‐based predictor , 2001, Protein science : a publication of the Protein Society.

[37]  B. Rost,et al.  A modified definition of Sov, a segment‐based measure for protein secondary structure prediction assessment , 1999, Proteins.

[38]  Piero Fariselli,et al.  A new decoding algorithm for hidden Markov models improves the prediction of the topology of all-beta membrane proteins , 2005, BMC Bioinformatics.

[39]  Pierre Baldi,et al.  Three-stage prediction of protein ?-sheets by neural networks, alignments and graph algorithms , 2005, ISMB.

[40]  Pierre Baldi,et al.  Assessing the accuracy of prediction algorithms for classification: an overview , 2000, Bioinform..

[41]  BaldiPierre,et al.  Three-stage prediction of protein β-sheets by neural networks, alignments and graph algorithms , 2005 .

[42]  M. Saier,et al.  The beta-barrel finder (BBF) program, allowing identification of outer membrane beta-barrel proteins encoded within prokaryotic genomes. , 2002, Protein science : a publication of the Protein Society.

[43]  References , 1971 .

[44]  Harpreet Kaur,et al.  Prediction of transmembrane regions of beta-barrel proteins using ANN- and SVM-based methods. , 2004, Proteins.

[45]  Stavros J. Hamodrakas,et al.  A Hidden Markov Model method, capable of predicting and discriminating β-barrel outer membrane proteins , 2004, BMC Bioinformatics.

[46]  J. Rosenbusch,et al.  Folding patterns of porin and bacteriorhodopsin. , 1985, The EMBO journal.

[47]  G. Schulz.  beta-Barrel membrane proteins. , 2000, Current opinion in structural biology.

[48]  L. Tamm,et al.  Folding and assembly of beta-barrel membrane proteins. , 2004, Biochimica et biophysica acta.

[49]  Stavros J. Hamodrakas,et al.  PRED-TMBB: a web server for predicting the topology of ?barrel outer membrane proteins , 2004, Nucleic Acids Res..

[50]  P K Ponnuswamy,et al.  Identification of membrane spanning beta strands in bacterial porins. , 1997, Protein engineering.

[51]  J. Skolnick,et al.  MONSSTER: a method for folding globular proteins with a small number of distance restraints. , 1997, Journal of molecular biology.

[52]  M. Michael Gromiha,et al.  A simple statistical method for discriminating outer membrane proteins with better accuracy , 2005, Bioinform..

[53]  Adam Zemla,et al.  Critical assessment of methods of protein structure prediction (CASP)‐round V , 2005, Proteins.

[54]  Pierre Baldi,et al.  Prediction of contact maps by GIOHMMs and recurrent neural networks using lateral propagation from all four cardinal corners , 2002, ISMB.

[55]  Shandar Ahmad,et al.  Neural network‐based prediction of transmembrane β‐strand segments in outer membrane proteins , 2004, J. Comput. Chem..

[56]  Makiko Suwa,et al.  Neural network-based prediction of transmembrane beta-strand segments in outer membrane proteins. , 2004, Journal of computational chemistry.

[57]  Pierre Baldi,et al.  DOMpro: Protein Domain Prediction Using Profiles, Secondary Structure, Relative Solvent Accessibility, and Recursive Neural Networks , 2006, Data Mining and Knowledge Discovery.

[58]  C Kooperberg,et al.  Assembly of protein tertiary structures from fragments with similar local sequences using simulated annealing and Bayesian scoring functions. , 1997, Journal of molecular biology.

[59]  Peter Clote,et al.  Predicting transmembrane β‐barrels and interstrand residue interactions from sequence , 2006, Proteins.