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1.  Template-based protein structure modeling using TASSERVMT 
Proteins  2011;10.1002/prot.23183.
Template-based protein structure modeling is commonly used for protein structure prediction. Based on the observation that multiple template-based methods often perform better than single template-based methods, we further explore the use of a variable number of multiple templates for a given target in the latest variant of TASSER, TASSERVMT. We first develop an algorithm that improves the target-template alignment for a given template. The improved alignment, called the SP3 alternative alignment, is generated by a parametric alignment method coupled with short TASSER refinement on models selected using knowledge-based scores. The refined top model is then structurally aligned to the template to produce the SP3 alternative alignment. Templates identified using SP3 threading are combined with the SP3 alternative and HHEARCH alignments to provide target alignments to each template. These template models are then grouped into sets containing a variable number of template/alignment combinations. For each set, we run short TASSER simulations to build full-length models. Then, the models from all sets of templates are pooled, and the top 20–50 models selected using FTCOM ranking method. These models are then subjected to a single longer TASSER refinement run for final prediction. We benchmarked our method by comparison with our previously developed approach, pro-sp3-TASSER, on a set with 874 Easy and 318 Hard targets. The average GDT-TS score improvements for the first model are 3.5% and 4.3% for Easy and Hard targets, respectively. When tested on the 112 CASP9 targets, our method improves the average GDT-TS scores as compared to pro-sp3-TASSER by 8.2% and 9.3% for the 80 Easy and 32 Hard targets, respectively. It also shows slightly better results than the top ranked CASP9 Zhang-Server, QUARK and HHpredA methods. The program is available for download at http://cssb.biology.gatech.edu/.
doi:10.1002/prot.23183
PMCID: PMC3291807  PMID: 22105797
template-based modeling; threading; alignment; SP3; TASSER
2.  Protein threading using context-specific alignment potential 
Bioinformatics  2013;29(13):i257-i265.
Motivation: Template-based modeling, including homology modeling and protein threading, is the most reliable method for protein 3D structure prediction. However, alignment errors and template selection are still the main bottleneck for current template-base modeling methods, especially when proteins under consideration are distantly related.
Results: We present a novel context-specific alignment potential for protein threading, including alignment and template selection. Our alignment potential measures the log-odds ratio of one alignment being generated from two related proteins to being generated from two unrelated proteins, by integrating both local and global context-specific information. The local alignment potential quantifies how well one sequence residue can be aligned to one template residue based on context-specific information of the residues. The global alignment potential quantifies how well two sequence residues can be placed into two template positions at a given distance, again based on context-specific information. By accounting for correlation among a variety of protein features and making use of context-specific information, our alignment potential is much more sensitive than the widely used context-independent or profile-based scoring function. Experimental results confirm that our method generates significantly better alignments and threading results than the best profile-based methods on several large benchmarks. Our method works particularly well for distantly related proteins or proteins with sparse sequence profiles because of the effective integration of context-specific, structure and global information.
Availability: http://raptorx.uchicago.edu/download/.
Contact: jinboxu@gmail.com
doi:10.1093/bioinformatics/btt210
PMCID: PMC3694651  PMID: 23812991
3.  A multiple-template approach to protein threading 
Proteins  2011;79(6):1930-1939.
Most threading methods predict the structure of a protein using only a single template. Due to the increasing number of solved structures, a protein without solved structure is very likely to have more than one similar template structures. Therefore, a natural question to ask is if we can improve modeling accuracy using multiple templates. This paper describes a new multiple-template threading method to answer this question. At the heart of this multiple-template threading method is a novel probabilistic-consistency algorithm that can accurately align a single protein sequence simultaneously to multiple templates. Experimental results indicate that our multiple-template method can improve pairwise sequence-template alignment accuracy and generate models with better quality than single-template models even if they are built from the best single templates (P-value<10-6) while many popular multiple sequence/structure alignment tools fail to do so. The underlying reason is that our probabilistic-consistency algorithm can generate accurate multiple sequence/template alignments. In another word, without an accurate multiple sequence/template alignment the modeling accuracy cannot be improved by simply using multiple templates to increase alignment coverage. Blindly tested on the CASP9 targets with more than one good template structures, our method outperforms all other CASP9 servers except two (Zhang-Server and QUARK of the same group). Our probabilistic-consistency algorithm can possibly be extended to align multiple protein/RNA sequences and structures.
doi:10.1002/prot.23016
PMCID: PMC3092796  PMID: 21465564
protein modeling; multiple-template threading; probabilistic alignment matrix; probabilistic-consistency algorithm; multiple sequence/template alignment
4.  Template-based and free modeling by RAPTOR++ in CASP8 
Proteins  2009;77(Suppl 9):133-137.
We developed and tested RAPTOR++ in CASP8 for protein structure prediction. RAPTOR++ contains four modules: threading, model quality assessment, multiple protein alignment and template-free modeling. RAPTOR++ first threads a target protein to all the templates using three methods and then predicts the quality of the 3D model implied by each alignment using a model quality assessment method. Based upon the predicted quality, RAPTOR++ employs different strategies as follows. If multiple alignments have good quality, RAPTOR++ builds a multiple protein alignment between the target and top templates and then generates a 3D model using MODELLER. If all the alignments have very low quality, RAPTOR++ uses template-free modeling. Otherwise, RAPTOR++ submits a threading-generated 3D model with the best quality. RAPTOR++ was not ready for the first 1/3 targets and was under development during the whole CASP8 season. The template-based and template-free modeling modules in RAPTOR++ are not closely integrated. We are using our template-free modeling technique to refine template-based models.
doi:10.1002/prot.22567
PMCID: PMC2785131  PMID: 19722267
template-based modeling; template-free modeling; protein threading; model quality assessment
5.  (PS)2-v2: template-based protein structure prediction server 
BMC Bioinformatics  2009;10:366.
Background
Template selection and target-template alignment are critical steps for template-based modeling (TBM) methods. To identify the template for the twilight zone of 15~25% sequence similarity between targets and templates is still difficulty for template-based protein structure prediction. This study presents the (PS)2-v2 server, based on our original server with numerous enhancements and modifications, to improve reliability and applicability.
Results
To detect homologous proteins with remote similarity, the (PS)2-v2 server utilizes the S2A2 matrix, which is a 60 × 60 substitution matrix using the secondary structure propensities of 20 amino acids, and the position-specific sequence profile (PSSM) generated by PSI-BLAST. In addition, our server uses multiple templates and multiple models to build and assess models. Our method was evaluated on the Lindahl benchmark for fold recognition and ProSup benchmark for sequence alignment. Evaluation results indicated that our method outperforms sequence-profile approaches, and had comparable performance to that of structure-based methods on these benchmarks. Finally, we tested our method using the 154 TBM targets of the CASP8 (Critical Assessment of Techniques for Protein Structure Prediction) dataset. Experimental results show that (PS)2-v2 is ranked 6th among 72 severs and is faster than the top-rank five serves, which utilize ab initio methods.
Conclusion
Experimental results demonstrate that (PS)2-v2 with the S2A2 matrix is useful for template selections and target-template alignments by blending the amino acid and structural propensities. The multiple-template and multiple-model strategies are able to significantly improve the accuracies for target-template alignments in the twilight zone. We believe that this server is useful in structure prediction and modeling, especially in detecting homologous templates with sequence similarity in the twilight zone.
doi:10.1186/1471-2105-10-366
PMCID: PMC2775752  PMID: 19878598
6.  Interplay of I-TASSER and QUARK for template-based and ab initio protein structure prediction in CASP10 
Proteins  2013;82(0 2):175-187.
We develop and test a new pipeline in CASP10 to predict protein structures based on an interplay of I-TASSER and QUARK for both free-modeling (FM) and template-based modeling (TBM) targets. The most noteworthy observation is that sorting through the threading template pool using the QUARK-based ab initio models as probes allows the detection of distant-homology templates which might be ignored by the traditional sequence profile-based threading alignment algorithms. Further template assembly refinement by I-TASSER resulted in successful folding of two medium-sized FM targets with >150 residues. For TBM, the multiple threading alignments from LOMETS are, for the first time, incorporated into the ab initio QUARK simulations, which were further refined by I-TASSER assembly refinement. Compared with the traditional threading assembly refinement procedures, the inclusion of the threading-constrained ab initio folding models can consistently improve the quality of the full-length models as assessed by the GDT-HA and hydrogen-bonding scores. Despite the success, significant challenges still exist in domain boundary prediction and consistent folding of medium-size proteins (especially beta-proteins) for nonhomologous targets. Further developments of sensitive fold-recognition and ab initio folding methods are critical for solving these problems.
doi:10.1002/prot.24341
PMCID: PMC4067246  PMID: 23760925
protein structure prediction; CASP10; threading; ab initio folding; I-TASSER; QUARK
7.  RaptorX: exploiting structure information for protein alignment by statistical inference 
Proteins  2011;79(Suppl 10):161-171.
This paper presents RaptorX, a statistical method for template-based protein modeling that improves alignment accuracy by exploiting structural information in a single or multiple templates. RaptorX consists of three major components: single-template threading, alignment quality prediction and multiple-template threading. This paper summarizes the methods employed by RaptorX and presents its CASP9 result analysis, aiming to identify major bottlenecks with RaptorX and template-based modeling and hopefully directions for further study. Our results show that template structural information helps a lot with both single-template and multiple-template protein threading especially when closely-related templates are unavailable and there is still large room for improvement in both alignment and template selection. The RaptorX web server is available at http://raptorx.uchicago.edu.
doi:10.1002/prot.23175
PMCID: PMC3226909  PMID: 21987485
single-template threading; multiple-template threading; alignment quality prediction; probabilistic alignment; multiple protein alignment; CASP
8.  GalaxyTBM: template-based modeling by building a reliable core and refining unreliable local regions 
BMC Bioinformatics  2012;13:198.
Background
Protein structures can be reliably predicted by template-based modeling (TBM) when experimental structures of homologous proteins are available. However, it is challenging to obtain structures more accurate than the single best templates by either combining information from multiple templates or by modeling regions that vary among templates or are not covered by any templates.
Results
We introduce GalaxyTBM, a new TBM method in which the more reliable core region is modeled first from multiple templates and less reliable, variable local regions, such as loops or termini, are then detected and re-modeled by an ab initio method. This TBM method is based on “Seok-server,” which was tested in CASP9 and assessed to be amongst the top TBM servers. The accuracy of the initial core modeling is enhanced by focusing on more conserved regions in the multiple-template selection and multiple sequence alignment stages. Additional improvement is achieved by ab initio modeling of up to 3 unreliable local regions in the fixed framework of the core structure. Overall, GalaxyTBM reproduced the performance of Seok-server, with GalaxyTBM and Seok-server resulting in average GDT-TS of 68.1 and 68.4, respectively, when tested on 68 single-domain CASP9 TBM targets. For application to multi-domain proteins, GalaxyTBM must be combined with domain-splitting methods.
Conclusion
Application of GalaxyTBM to CASP9 targets demonstrates that accurate protein structure prediction is possible by use of a multiple-template-based approach, and ab initio modeling of variable regions can further enhance the model quality.
doi:10.1186/1471-2105-13-198
PMCID: PMC3462707  PMID: 22883815
Protein structure prediction; Model refinement; Loop modeling; Terminus modeling
9.  Improving consensus contact prediction via server correlation reduction 
Background
Protein inter-residue contacts play a crucial role in the determination and prediction of protein structures. Previous studies on contact prediction indicate that although template-based consensus methods outperform sequence-based methods on targets with typical templates, such consensus methods perform poorly on new fold targets. However, we find out that even for new fold targets, the models generated by threading programs can contain many true contacts. The challenge is how to identify them.
Results
In this paper, we develop an integer linear programming model for consensus contact prediction. In contrast to the simple majority voting method assuming that all the individual servers are equally important and independent, the newly developed method evaluates their correlation by using maximum likelihood estimation and extracts independent latent servers from them by using principal component analysis. An integer linear programming method is then applied to assign a weight to each latent server to maximize the difference between true contacts and false ones. The proposed method is tested on the CASP7 data set. If the top L/5 predicted contacts are evaluated where L is the protein size, the average accuracy is 73%, which is much higher than that of any previously reported study. Moreover, if only the 15 new fold CASP7 targets are considered, our method achieves an average accuracy of 37%, which is much better than that of the majority voting method, SVM-LOMETS, SVM-SEQ, and SAM-T06. These methods demonstrate an average accuracy of 13.0%, 10.8%, 25.8% and 21.2%, respectively.
Conclusion
Reducing server correlation and optimally combining independent latent servers show a significant improvement over the traditional consensus methods. This approach can hopefully provide a powerful tool for protein structure refinement and prediction use.
doi:10.1186/1472-6807-9-28
PMCID: PMC2689239  PMID: 19419562
10.  ThreaDom: extracting protein domain boundary information from multiple threading alignments 
Bioinformatics  2013;29(13):i247-i256.
Motivation: Protein domains are subunits that can fold and evolve independently. Identification of domain boundary locations is often the first step in protein folding and function annotations. Most of the current methods deduce domain boundaries by sequence-based analysis, which has low accuracy. There is no efficient method for predicting discontinuous domains that consist of segments from separated sequence regions. As template-based methods are most efficient for protein 3D structure modeling, combining multiple threading alignment information should increase the accuracy and reliability of computational domain predictions.
Result: We developed a new protein domain predictor, ThreaDom, which deduces domain boundary locations based on multiple threading alignments. The core of the method development is the derivation of a domain conservation score that combines information from template domain structures and terminal and internal alignment gaps. Tested on 630 non-redundant sequences, without using homologous templates, ThreaDom generates correct single- and multi-domain classifications in 81% of cases, where 78% have the domain linker assigned within ±20 residues. In a second test on 486 proteins with discontinuous domains, ThreaDom achieves an average precision 84% and recall 65% in domain boundary prediction. Finally, ThreaDom was examined on 56 targets from CASP8 and had a domain overlap rate 73, 87 and 85% with the target for Free Modeling, Hard multiple-domain and discontinuous domain proteins, respectively, which are significantly higher than most domain predictors in the CASP8. Similar results were achieved on the targets from the most recently CASP9 and CASP10 experiments.
Availability: http://zhanglab.ccmb.med.umich.edu/ThreaDom/.
Contact: zhng@umich.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btt209
PMCID: PMC3694664  PMID: 23812990
11.  I-TASSER: Fully automated protein structure prediction in CASP8 
Proteins  2009;77(Suppl 9):100-113.
The I-TASSER algorithm for protein 3D structure prediction was tested in CASP8, with the procedure fully automated in both the Server and Human sections. The quality of the server models is close to that of human ones but incorporating more diverse templates from other servers improves the results of human predictions in the distant homology category. For the first time, the sequence-based contact predictions from machine learning techniques are found helpful for both template-based modeling (TBM) and template-free modeling (FM). In TBM, although the average accuracy of the sequence-based contact predictions is lower than that from template-based ones, the novel contacts in the sequence-based predictions, which are complementary to the threading templates in the weakly or unaligned regions, are important to improve the global and local packing of these regions. Moreover, the newly developed atomic structural refinement algorithm was tested in CASP8 and found to improve the hydrogen-bonding networks and the overall TM-score, which is mainly due to its ability of removing steric clashes so that the models can be generated from cluster centroids. Nevertheless, one of the major issues of the I-TASSER pipeline is the model selection where the best models could not be appropriately recognized when the correct templates are detected only by the minority of the threading algorithms. There are also problems related with domain-splitting and mirror image recognition which mainly influences the performance of I-TASSER modeling in the FM-based structure predictions.
doi:10.1002/prot.22588
PMCID: PMC2782770  PMID: 19768687
Protein structure prediction; threading; I-TASSER; CASP8; contact prediction; free modeling
12.  CaspR: a web server for automated molecular replacement using homology modelling 
Nucleic Acids Research  2004;32(Web Server issue):W606-W609.
Molecular replacement (MR) is the method of choice for X-ray crystallography structure determination when structural homologues are available in the Protein Data Bank (PDB). Although the success rate of MR decreases sharply when the sequence similarity between template and target proteins drops below 35% identical residues, it has been found that screening for MR solutions with a large number of different homology models may still produce a suitable solution where the original template failed. Here we present the web tool CaspR, implementing such a strategy in an automated manner. On input of experimental diffraction data, of the corresponding target sequence and of one or several potential templates, CaspR executes an optimized molecular replacement procedure using a combination of well-established stand-alone software tools. The protocol of model building and screening begins with the generation of multiple structure–sequence alignments produced with T-COFFEE, followed by homology model building using MODELLER, molecular replacement with AMoRe and model refinement based on CNS. As a result, CaspR provides a progress report in the form of hierarchically organized summary sheets that describe the different stages of the computation with an increasing level of detail. For the 10 highest-scoring potential solutions, pre-refined structures are made available for download in PDB format. Results already obtained with CaspR and reported on the web server suggest that such a strategy significantly increases the fraction of protein structures which may be solved by MR. Moreover, even in situations where standard MR yields a solution, pre-refined homology models produced by CaspR significantly reduce the time-consuming refinement process. We expect this automated procedure to have a significant impact on the throughput of large-scale structural genomics projects. CaspR is freely available at http://igs-server.cnrs-mrs.fr/Caspr/.
doi:10.1093/nar/gkh400
PMCID: PMC441538  PMID: 15215460
13.  A conditional neural fields model for protein threading 
Bioinformatics  2012;28(12):i59-i66.
Motivation: Alignment errors are still the main bottleneck for current template-based protein modeling (TM) methods, including protein threading and homology modeling, especially when the sequence identity between two proteins under consideration is low (<30%).
Results: We present a novel protein threading method, CNFpred, which achieves much more accurate sequence–template alignment by employing a probabilistic graphical model called a Conditional Neural Field (CNF), which aligns one protein sequence to its remote template using a non-linear scoring function. This scoring function accounts for correlation among a variety of protein sequence and structure features, makes use of information in the neighborhood of two residues to be aligned, and is thus much more sensitive than the widely used linear or profile-based scoring function. To train this CNF threading model, we employ a novel quality-sensitive method, instead of the standard maximum-likelihood method, to maximize directly the expected quality of the training set. Experimental results show that CNFpred generates significantly better alignments than the best profile-based and threading methods on several public (but small) benchmarks as well as our own large dataset. CNFpred outperforms others regardless of the lengths or classes of proteins, and works particularly well for proteins with sparse sequence profiles due to the effective utilization of structure information. Our methodology can also be adapted to protein sequence alignment.
Contact: j3xu@ttic.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/bts213
PMCID: PMC3371845  PMID: 22689779
14.  A Protocol for Computer-Based Protein Structure and Function Prediction 
Genome sequencing projects have ciphered millions of protein sequence, which require knowledge of their structure and function to improve the understanding of their biological role. Although experimental methods can provide detailed information for a small fraction of these proteins, computational modeling is needed for the majority of protein molecules which are experimentally uncharacterized. The I-TASSER server is an on-line workbench for high-resolution modeling of protein structure and function. Given a protein sequence, a typical output from the I-TASSER server includes secondary structure prediction, predicted solvent accessibility of each residue, homologous template proteins detected by threading and structure alignments, up to five full-length tertiary structural models, and structure-based functional annotations for enzyme classification, Gene Ontology terms and protein-ligand binding sites. All the predictions are tagged with a confidence score which tells how accurate the predictions are without knowing the experimental data. To facilitate the special requests of end users, the server provides channels to accept user-specified inter-residue distance and contact maps to interactively change the I-TASSER modeling; it also allows users to specify any proteins as template, or to exclude any template proteins during the structure assembly simulations. The structural information could be collected by the users based on experimental evidences or biological insights with the purpose of improving the quality of I-TASSER predictions. The server was evaluated as the best programs for protein structure and function predictions in the recent community-wide CASP experiments. There are currently >20,000 registered scientists from over 100 countries who are using the on-line I-TASSER server.
doi:10.3791/3259
PMCID: PMC3308591  PMID: 22082966
15.  MUSTER: Improving protein sequence profile–profile alignments by using multiple sources of structure information 
Proteins  2008;72(2):547-556.
We develop a new threading algorithm MUSTER by extending the previous sequence profile–profile alignment method, PPA. It combines various sequence and structure information into single-body terms which can be conveniently used in dynamic programming search: (1) sequence profiles; (2) secondary structures; (3) structure fragment profiles; (4) solvent accessibility; (5) dihedral torsion angles; (6) hydrophobic scoring matrix. The balance of the weighting parameters is optimized by a grading search based on the average TM-score of 111 training proteins which shows a better performance than using the conventional optimization methods based on the PROSUP data-base. The algorithm is tested on 500 nonhomologous proteins independent of the training sets. After removing the homologous templates with a sequence identity to the target >30%, in 224 cases, the first template alignment has the correct topology with a TM-score >0.5. Even with a more stringent cutoff by removing the templates with a sequence identity >20% or detectable by PSI-BLAST with an E-value <0.05, MUSTER is able to identify correct folds in 137 cases with the first model of TM-score >0.5. Dependent on the homology cutoffs, the average TM-score of the first threading alignments by MUSTER is 5.1–6.3% higher than that by PPA. This improvement is statistically significant by the Wilcoxon signed rank test with a P-value < 1.0 × 10−13, which demonstrates the effect of additional structural information on the protein fold recognition. The MUSTER server is freely available to the academic community at http://zhang.bioinformatics.ku.edu/MUSTER.
doi:10.1002/prot.21945
PMCID: PMC2666101  PMID: 18247410
threading; protein structure prediction; TM-score; solvent accessibility; dihedral angle prediction; hydrophobic scoring matrix
16.  Ab initio modeling of small proteins by iterative TASSER simulations 
BMC Biology  2007;5:17.
Background
Predicting 3-dimensional protein structures from amino-acid sequences is an important unsolved problem in computational structural biology. The problem becomes relatively easier if close homologous proteins have been solved, as high-resolution models can be built by aligning target sequences to the solved homologous structures. However, for sequences without similar folds in the Protein Data Bank (PDB) library, the models have to be predicted from scratch. Progress in the ab initio structure modeling is slow. The aim of this study was to extend the TASSER (threading/assembly/refinement) method for the ab initio modeling and examine systemically its ability to fold small single-domain proteins.
Results
We developed I-TASSER by iteratively implementing the TASSER method, which is used in the folding test of three benchmarks of small proteins. First, data on 16 small proteins (< 90 residues) were used to generate I-TASSER models, which had an average Cα-root mean square deviation (RMSD) of 3.8Å, with 6 of them having a Cα-RMSD < 2.5Å. The overall result was comparable with the all-atomic ROSETTA simulation, but the central processing unit (CPU) time by I-TASSER was much shorter (150 CPU days vs. 5 CPU hours). Second, data on 20 small proteins (< 120 residues) were used. I-TASSER folded four of them with a Cα-RMSD < 2.5Å. The average Cα-RMSD of the I-TASSER models was 3.9Å, whereas it was 5.9Å using TOUCHSTONE-II software. Finally, 20 non-homologous small proteins (< 120 residues) were taken from the PDB library. An average Cα-RMSD of 3.9Å was obtained for the third benchmark, with seven cases having a Cα-RMSD < 2.5Å.
Conclusion
Our simulation results show that I-TASSER can consistently predict the correct folds and sometimes high-resolution models for small single-domain proteins. Compared with other ab initio modeling methods such as ROSETTA and TOUCHSTONE II, the average performance of I-TASSER is either much better or is similar within a lower computational time. These data, together with the significant performance of automated I-TASSER server (the Zhang-Server) in the 'free modeling' section of the recent Critical Assessment of Structure Prediction (CASP)7 experiment, demonstrate new progresses in automated ab initio model generation. The I-TASSER server is freely available for academic users .
doi:10.1186/1741-7007-5-17
PMCID: PMC1878469  PMID: 17488521
17.  Optimal contact map alignment of protein–protein interfaces 
Bioinformatics  2008;24(20):2324-2328.
The long-standing problem of constructing protein structure alignments is of central importance in computational biology. The main goal is to provide an alignment of residue correspondences, in order to identify homologous residues across chains. A critical next step of this is the alignment of protein complexes and their interfaces. Here, we introduce the program CMAPi, a two-dimensional dynamic programming algorithm that, given a pair of protein complexes, optimally aligns the contact maps of their interfaces: it produces polynomial-time near-optimal alignments in the case of multiple complexes. We demonstrate the efficacy of our algorithm on complexes from PPI families listed in the SCOPPI database and from highly divergent cytokine families. In comparison to existing techniques, CMAPi generates more accurate alignments of interacting residues within families of interacting proteins, especially for sequences with low similarity. While previous methods that use an all-atom based representation of the interface have been successful, CMAPi's use of a contact map representation allows it to be more tolerant to conformational changes and thus to align more of the interaction surface. These improved interface alignments should enhance homology modeling and threading methods for predicting PPIs by providing a basis for generating template profiles for sequence–structure alignment.
Contact: bab@mit.edu; jbienkowska@gmail.com
Supplementary information: Supplementary data are available at http://theory.csail.mit.edu/cmapi
doi:10.1093/bioinformatics/btn432
PMCID: PMC2562013  PMID: 18710876
18.  The utility of geometrical and chemical restraint information extracted from predicted ligand binding sites in protein structure refinement 
Journal of structural biology  2010;173(3):558-569.
Exhaustive exploration of molecular interactions at the level of complete proteomes requires efficient and reliable computational approaches to protein function inference. Ligand docking and ranking techniques show considerable promise in their ability to quantify the interactions between proteins and small molecules. Despite the advances in the development of docking approaches and scoring functions, the genome-wide application of many ligand docking/screening algorithms is limited by the quality of the binding sites in theoretical receptor models constructed by protein structure prediction. In this study, we describe a new template-based method for the local refinement of ligand-binding regions in protein models using remotely related templates identified by threading. We designed a Support Vector Regression (SVR) model that selects correct binding site geometries in a large ensemble of multiple receptor conformations. The SVR model employs several scoring functions that impose geometrical restraints on the Cα positions, account for the specific chemical environment within a binding site and optimize the interactions with putative ligands. The SVR score is well correlated with the RMSD from the native structure; in 47% (70%) of the cases, the Pearson’s correlation coefficient is >0.5 (>0.3). When applied to weakly homologous models, the average heavy atom, local RMSD from the native structure of the top-ranked (best of top five) binding site geometries is 3.1 Å (2.9 Å) for roughly half of the targets; this represents a 0.1 (0.3) Å average improvement over the original predicted structure. Focusing on the subset of strongly conserved residues, the average heavy atom RMSD is 2.6 Å (2.3 Å). Furthermore, we estimate the upper bound of template-based binding site refinement using only weakly related proteins to be ~2.6 Å RMSD. This value also corresponds to the plasticity of the ligand-binding regions in distant homologues. The Binding Site Refinement (BSR) approach is available to the scientific community as a web server that can be accessed at http://cssb.biology.gatech.edu/bsr/.
doi:10.1016/j.jsb.2010.09.009
PMCID: PMC3036769  PMID: 20850544
Ligand-binding site refinement; proteinthreading; protein structure prediction; ligand-binding site prediction; ensemble docking; molecular function
19.  MULTICOM: a multi-level combination approach to protein structure prediction and its assessments in CASP8 
Bioinformatics  2010;26(7):882-888.
Motivation: Protein structure prediction is one of the most important problems in structural bioinformatics. Here we describe MULTICOM, a multi-level combination approach to improve the various steps in protein structure prediction. In contrast to those methods which look for the best templates, alignments and models, our approach tries to combine complementary and alternative templates, alignments and models to achieve on average better accuracy.
Results: The multi-level combination approach was implemented via five automated protein structure prediction servers and one human predictor which participated in the eighth Critical Assessment of Techniques for Protein Structure Prediction (CASP8), 2008. The MULTICOM servers and human predictor were consistently ranked among the top predictors on the CASP8 benchmark. The methods can predict moderate- to high-resolution models for most template-based targets and low-resolution models for some template-free targets. The results show that the multi-level combination of complementary templates, alternative alignments and similar models aided by model quality assessment can systematically improve both template-based and template-free protein modeling.
Availability: The MULTICOM server is freely available at http://casp.rnet.missouri.edu/multicom_3d.html
Contact: chengji@missouri.edu
doi:10.1093/bioinformatics/btq058
PMCID: PMC2844995  PMID: 20150411
20.  GalaxyWEB server for protein structure prediction and refinement 
Nucleic Acids Research  2012;40(Web Server issue):W294-W297.
Three-dimensional protein structures provide invaluable information for understanding and regulating biological functions of proteins. The GalaxyWEB server predicts protein structure from sequence by template-based modeling and refines loop or terminus regions by ab initio modeling. This web server is based on the method tested in CASP9 (9th Critical Assessment of techniques for protein Structure Prediction) as ‘Seok-server’, which was assessed to be among top performing template-based modeling servers. The method generates reliable core structures from multiple templates and re-builds unreliable loops or termini by using an optimization-based refinement method. In addition to structure prediction, a user can also submit a refinement only job by providing a starting model structure and locations of loops or termini to refine. The web server can be freely accessed at http://galaxy.seoklab.org/.
doi:10.1093/nar/gks493
PMCID: PMC3394311  PMID: 22649060
21.  I-TASSER server for protein 3D structure prediction 
BMC Bioinformatics  2008;9:40.
Background
Prediction of 3-dimensional protein structures from amino acid sequences represents one of the most important problems in computational structural biology. The community-wide Critical Assessment of Structure Prediction (CASP) experiments have been designed to obtain an objective assessment of the state-of-the-art of the field, where I-TASSER was ranked as the best method in the server section of the recent 7th CASP experiment. Our laboratory has since then received numerous requests about the public availability of the I-TASSER algorithm and the usage of the I-TASSER predictions.
Results
An on-line version of I-TASSER is developed at the KU Center for Bioinformatics which has generated protein structure predictions for thousands of modeling requests from more than 35 countries. A scoring function (C-score) based on the relative clustering structural density and the consensus significance score of multiple threading templates is introduced to estimate the accuracy of the I-TASSER predictions. A large-scale benchmark test demonstrates a strong correlation between the C-score and the TM-score (a structural similarity measurement with values in [0, 1]) of the first models with a correlation coefficient of 0.91. Using a C-score cutoff > -1.5 for the models of correct topology, both false positive and false negative rates are below 0.1. Combining C-score and protein length, the accuracy of the I-TASSER models can be predicted with an average error of 0.08 for TM-score and 2 Å for RMSD.
Conclusion
The I-TASSER server has been developed to generate automated full-length 3D protein structural predictions where the benchmarked scoring system helps users to obtain quantitative assessments of the I-TASSER models. The output of the I-TASSER server for each query includes up to five full-length models, the confidence score, the estimated TM-score and RMSD, and the standard deviation of the estimations. The I-TASSER server is freely available to the academic community at .
doi:10.1186/1471-2105-9-40
PMCID: PMC2245901  PMID: 18215316
22.  FunFOLD: an improved automated method for the prediction of ligand binding residues using 3D models of proteins 
BMC Bioinformatics  2011;12:160.
Background
The accurate prediction of ligand binding residues from amino acid sequences is important for the automated functional annotation of novel proteins. In the previous two CASP experiments, the most successful methods in the function prediction category were those which used structural superpositions of 3D models and related templates with bound ligands in order to identify putative contacting residues. However, whilst most of this prediction process can be automated, visual inspection and manual adjustments of parameters, such as the distance thresholds used for each target, have often been required to prevent over prediction. Here we describe a novel method FunFOLD, which uses an automatic approach for cluster identification and residue selection. The software provided can easily be integrated into existing fold recognition servers, requiring only a 3D model and list of templates as inputs. A simple web interface is also provided allowing access to non-expert users. The method has been benchmarked against the top servers and manual prediction groups tested at both CASP8 and CASP9.
Results
The FunFOLD method shows a significant improvement over the best available servers and is shown to be competitive with the top manual prediction groups that were tested at CASP8. The FunFOLD method is also competitive with both the top server and manual methods tested at CASP9. When tested using common subsets of targets, the predictions from FunFOLD are shown to achieve a significantly higher mean Matthews Correlation Coefficient (MCC) scores and Binding-site Distance Test (BDT) scores than all server methods that were tested at CASP8. Testing on the CASP9 set showed no statistically significant separation in performance between FunFOLD and the other top server groups tested.
Conclusions
The FunFOLD software is freely available as both a standalone package and a prediction server, providing competitive ligand binding site residue predictions for expert and non-expert users alike. The software provides a new fully automated approach for structure based function prediction using 3D models of proteins.
doi:10.1186/1471-2105-12-160
PMCID: PMC3123233  PMID: 21575183
23.  Improving protein fold recognition and template-based modeling by employing probabilistic-based matching between predicted one-dimensional structural properties of query and corresponding native properties of templates 
Bioinformatics  2011;27(15):2076-2082.
Motivation: In recent years, development of a single-method fold-recognition server lags behind consensus and multiple template techniques. However, a good consensus prediction relies on the accuracy of individual methods. This article reports our efforts to further improve a single-method fold recognition technique called SPARKS by changing the alignment scoring function and incorporating the SPINE-X techniques that make improved prediction of secondary structure, backbone torsion angle and solvent accessible surface area.
Results: The new method called SPARKS-X was tested with the SALIGN benchmark for alignment accuracy, Lindahl and SCOP benchmarks for fold recognition, and CASP 9 blind test for structure prediction. The method is compared to several state-of-the-art techniques such as HHPRED and BoostThreader. Results show that SPARKS-X is one of the best single-method fold recognition techniques. We further note that incorporating multiple templates and refinement in model building will likely further improve SPARKS-X.
Availability: The method is available as a SPARKS-X server at http://sparks.informatics.iupui.edu/
Contact: yqzhou@iupui.edu
doi:10.1093/bioinformatics/btr350
PMCID: PMC3137224  PMID: 21666270
24.  Automated protein structure modeling in CASP9 by I-TASSER pipeline combined with QUARK-based ab initio folding and FG-MD-based structure refinement 
Proteins  2011;79(Suppl 10):147-160.
I-TASSER is an automated pipeline for protein tertiary structure prediction using multiple threading alignments and iterative structure assembly simulations. In CASP9 experiments, two new algorithms, QUARK and FG-MD, were added to the I-TASSER pipeline for improving the structural modeling accuracy. QUARK is a de novo structure prediction algorithm used for structure modeling of proteins that lack detectable template structures. For distantly homologous targets, QUARK models are found useful as a reference structure for selecting good threading alignments and guiding the I-TASSER structure assembly simulations. FG-MD is an atomic-level structural refinement program that uses structural fragments collected from the PDB structures to guide molecular dynamics simulation and improve the local structure of predicted model, including hydrogen-bonding networks, torsion angles and steric clashes. Despite considerable progress in both the template-based and template-free structure modeling, significant improvements on protein target classification, domain parsing, model selection, and ab initio folding of beta-proteins are still needed to further improve the I-TASSER pipeline.
doi:10.1002/prot.23111
PMCID: PMC3228277  PMID: 22069036
protein structure prediction; threading; contact prediction; ab initio folding; CASP
25.  PDBalert: automatic, recurrent remote homology tracking and protein structure prediction 
Background
During the last years, methods for remote homology detection have grown more and more sensitive and reliable. Automatic structure prediction servers relying on these methods can generate useful 3D models even below 20% sequence identity between the protein of interest and the known structure (template). When no homologs can be found in the protein structure database (PDB), the user would need to rerun the same search at regular intervals in order to make timely use of a template once it becomes available.
Results
PDBalert is a web-based automatic system that sends an email alert as soon as a structure with homology to a protein in the user's watch list is released to the PDB database or appears among the sequences on hold. The mail contains links to the search results and to an automatically generated 3D homology model. The sequence search is performed with the same software as used by the very sensitive and reliable remote homology detection server HHpred, which is based on pairwise comparison of Hidden Markov models.
Conclusion
PDBalert will accelerate the information flow from the PDB database to all those who can profit from the newly released protein structures for predicting the 3D structure or function of their proteins of interest.
doi:10.1186/1472-6807-8-51
PMCID: PMC2605448  PMID: 19025670

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