- Methodology article
- Open Access
(PS)2-v2: template-based protein structure prediction server
© Chen et al; licensee BioMed Central Ltd. 2009
- Received: 29 June 2009
- Accepted: 31 October 2009
- Published: 31 October 2009
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.
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.
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.
- Protein Structure Prediction
- Amino Acid Type
- Fold Recognition
- Position Specific Score Matrix
- Protein Data Bank Code
For template-based modeling (TBM) and fold recognition methods, a prediction model can be built based on the coordinates of the appropriate template(s) . These approaches generally involve four steps: 1) a representative protein structure database is searched to identify a template that is structurally similar to the protein target; 2) an alignment between the target and the template is generated that should align equivalent residues together as in the case of a structural alignment; 3) a prediction structure of the target is built based on the alignment and the selected template structure, and 4) model quality evaluation. The first two steps significantly affect the quality of the final model prediction in TBM methods.
The secondary structure of a protein is often more conserved than the amino acid sequence, and the prediction accuracy of the secondary structure has been achieved ~80% on average. Recently, a number of methods, integrating secondary structures (i.e., α-helix, β-strand and coil) with primary amino acid sequences, have successfully detected the homologs with remote similarity for automated comparative modeling [2–6] and fold recognition [7–12]. These methods often used two separated substitution matrices [9, 10, 13] to score secondary structures and primary amino acids, respectively, for aligning a residue pair. The separated matrices are unable to reflect the real score because the amino acid type often prefers to a specific secondary structure.
Here, we have developed a substitution matrix, called S2A2, which considers the properties of the secondary structures and amino acid types. The S2A2 is a 60 × 60 matrix that considers all possible pair combination of 20 amino acid types and three secondary structure elements. This matrix was evaluated on the Lindahl benchmark  for fold recognition and the ProSup benchmark  for alignment accuracies. According to these evaluation results, the S2A2 matrix has higher accuracy than position specific scoring matrix (PSSM) generated by PSI-BLAST and prof_sim for fold recognition and sequence alignments. By integrating the S2A2 matrix and PSSM, each having a unique scoring mechanism, the (PS)2-v2 server blends the sequence profile and secondary structure information so that they work cooperatively.
The essential differences of (PS)2-original, (PS)2-CASP8 and (PS)2-v2
1. Template search
Consensus of PSI-BLAST and IMPALA
S2A2+PSSM with a self-developed aligned tool using dynamic programming
S2A2+PSSM with a modified SSEARCH program 
2. Target-template alignment
Consensus of PSI-BLAST, IMPALA and T-coffee
S2A2+PSSM with a self-developed aligned tool using dynamic programming
S2A2+PSSM with a modified SSEARCH program 
4. Model building
MODELLER with single model
MODELLER with single model
MODELLER with multiple models
5. Model evaluation
A substitution matrix is the key component of protein sequence alignment methods. We developed the S2A2 substitution matrix (Figure 3 and Figure S1 in Additional file 2) applying a general mathematical structure . To calculate the S2A2, 674 structural pairs (1,348 proteins) , which are structurally similar and with low sequence identity, were selected from SCOP 1.65  based on two criteria: 1) the root-mean-square deviation (rmsd) of a protein pair was be less than 3.5 Å, with more than 70% of aligned residues included in the rmsd calculation, and 2) the sequence identity of a pair is less than 40%. The selected protein pairs had an average sequence identity of 26%, an average rmsd of 2.3 Å and average aligned residues of 90% (207,492 aligned residues out of 230,915 residues). The program DSSP was used to assign the secondary structure for each residue of these 674 structural pairs. The eight types of the secondary structure used in DSSP were reduced to three commonly accepted types (H (helix), E (strand) and C (coil)) according to the following scheme: (H, G, I) → H; (E, B) → E; (T, S, blank) → C. The 20 amino acid types and 3 secondary structure types were converted into 60 residue-structure (RS) types.
Scoring and alignment methods
where i and j are RS letters on the query and the template, respectively; w stru (i, j) is a structure-dependent scoring weight, and is set to 1.3, 1.7 and 0.8 for α-helix, β-strand and coil, respectively; w S2A2 (here, w S2A2 is set to 0.64) is the weight of the S2A2 matrix; S2A2(i, j) and PSSM query (i, j) are the scores of S2A2 and PSSM matrices, respectively, when the RS letter i is aligned to the RS letter j. In addition, we considered structure-dependent gap penalty. Here, w gap is a structure-dependent gapping weight, set to 2.0 (α-helix), 2.0 (β-strand) and 0.15 (coil), respectively; g S2A2 is the gap opening penalty (set to 7.2) and the gap extension (set to 1.2) for the S2A2 matrix. These weights were optimized based on the SALIGN set. g pssm refers to the PSSM, where the gap opening penalty is 11 and gap extension is 1 according to the default parameters of PSI-BLAST.
Statistics and template selection
SSEARCH provides the statistical significance for library searches. The local sequence similarity score (S) follows the extreme value distribution, so that P(S > x) = 1 - exp(-Kmn exp(-λx)) where m, n are the lengths of the query and library sequence. The score shows that the average score for an unrelated library sequence increases with the logarithm of the length of the library sequence. SSEARCH uses simple linear regression against the log of the library sequence length to calculate a normalized "z-score" with mean 50, regardless of library sequence length, and variance 10. These z-scores can then be used with the extreme value distribution and the Poisson distribution to calculate the number of library sequences to obtain a score (i.e. E-value) greater than or equal to the score obtained in the search. The top-ranking 5 templates with the lowest E-values were considered as the templates if the E-values < 0.1. For each structure in the top-ranking 5 templates, The (PS)2-v2 server generated six alternative target-template alignments by using different S2A2-matrix (w S2A2 ) weights, including 0, 0.2, 0.4, 0.64, 0.8 and 1.0. Finally, we yielded 30 target-template alignments for a target protein.
Model building and evaluation
Protein structure models were built using the homology modeling tool, MODELLER  according to the selected template(s) and target-template alignment(s) and then the ability to discriminate a correct protein model from incorrect models is critical when a server used multiple model methods. Here, we utilized the program ProQ  to assess the quality of protein models based on the LGscore  and a model was considered correct if the LGscore was greater than 1.5 . The (PS)2-v2 server first selected the protein model, generated by the first rank template with w S2A2 = 0.64 as the seed model. The LGscore of the seed model was then compared with those of the other models based on the top-rank 5 templates with different w S2A2 weights. A model was chosen as the final one if it had the highest LGscore and its LGscore (> 0.7) was significantly better than that of the seed model. Otherwise, the server selected the seed model as the final model.
(PS)2-v2 considered a target as a multiple domain protein if any region with >40 residues has non-aligned residues to the template(s) when using above "model building and evaluation" steps. For a multiple domain protein, (PS)2-v2 automatically decided domain boundaries based on the borders of the large gaps between the target and the template(s), and repeatedly executed above steps to model the structures of the non-aligned residues (Figure 1). Finally, these multiple models were then used as structure templates to generate the full-length final model for the query protein.
The (PS)2-v2 server is an easy-to-use web server (Figure 2). Users input the query protein sequence in FASTA format. The server provides three modes (Automatic, Manual and 'Use this template') for choosing template(s) (Figure 2A). The default mode is 'Automatic'. In this mode, (PS)2-v2 automatically selects the modeling template(s). For the 'Manual' mode, our server enables users to assign specific template(s) from a list of candidates (Figure 2B). The 'Use this template' mode allows users to assign a specific protein structure as the template. Finally, (PS)2-v2 transmits the predicted results to the users by email addresses.
The (PS)2-v2 server typically yields a predicted structure within 7 minutes if the query sequence length is ~200. The server shows a list of templates, selected template(s), target-template alignment(s), predicted structure(s) and structure evaluations (Figures 2B and 2C). The predicted structures are visualized in PNG format generated by the MolScript  and Raster3D  packages. If the user clicks a PNG picture, then the corresponding protein 3D structure is also displayed on the AstexViewer  (Figure 2D). A user can download the predicted structure coordinates in the PDB format. The server also provides the target-template alignments and the structure quality factors (Figure 2E).
Modeling of ever shorter telomeres 3
The ever shorter telomeres 3 (Est3, UniProt Q03096), which is essential for telomere replication in vivo, is a small regulatory subunit of telomerase from Saccharomyces cerevisiae. According to structure prediction combined with in vivo characterization, it has been reported that Est3 consists of a predicted OB-fold (oligosaccharide/oligonucleotide binding) with structurally similar to the OB-fold of the human Tpp1 protein . Because of the limited degree of conservation between these two protein families, these two proteins could not be recognized from simple sequence profile methods. Additionally, the original (PS)2 -v2 server could not recognize them.
For the target Est3, the (PS)2 -v2 server selected the OB-fold domain of the Tpp1 protein (PDB code 2i46) from Homo sapiens as the template , with an E-value of 0.014. This template shared only 17.6% sequence identity with the query sequence. Figure 2C shows the target-template alignment. The server successfully recognized Tpp1 as the template since the secondary structure identity between the template and Est3 was 66.7%. Our method could align together three conserved residues (i.e. Trp21/Trp98, Asp86/Asp148 and Leu155/Leu204, in Est3 versus Tpp1; green blocks in Figure 2C), which are primarily involved in protein folding and/or stability of the OB-fold. Seven amino acid positions (yellow blocks in Figure 2C), which are structurally similar between the two protein families, were also aligned. These 10 aligned residues, depicted in cyan, are clustered in the interior of the core of the OB-fold (Figure 2D).
In the template-based protein structure prediction, the template selection and the target-template alignment are the two critical steps, since they will significantly affect the quality of the final model prediction. The template selections and the sequence alignments of the proposed method with the S2A2 matrix were evaluated by the Lindahl benchmark  and ProSup benchmark , respectively. In general, it is neither straightforward nor completely fair to compare the results of different fold-recognition and alignment methods given that each employs different sequence databases for sequence profiles, structure databases for structure profiles and properties, release dates, and scoring functions. Therefore, the comparisons between our methods and other published methods serve as an approximate guide. Here, we evaluated S2A2 matrix, PSI-BLAST and prof_sim using the same sequence database, UniRef90 , with the same parameters to generate a PSSM for fold recognitions (Lindahl benchmark) and sequence alignment (ProSup benchmark). Furthermore, (PS)2-v2 was assessed and compared with other 71 automatic servers on 154 TBM targets in CASP8. Please note that (PS)2-v2 did not participate in the CASP8 experiment.
Evaluation of S2A2 matrix
The S2A2 matrix (60 × 60) offers insights about substitution preferences of RS letters between homologous protein sequences (Figure 3 and Figure S1 in Additional file 2). The highest substitution score in this matrix is for the alignment of a RS letter 'Wβ' with a RS letter 'Wβ', where Wβ is the residue Trp with the β-strand structure (Figure S1 in Additional file 2). This substitution score is 6.2. In addition, the substitution scores are also high when two identical structural letters (e.g., diagonal entries) are aligned. For example, the alignment scores are 5.6 and 6.1 while 'Wα' and 'Cα' are aligned with 'Wα' and 'Cβ', respectively; where Wα is the residue Trp with the α-helix structure and Cα represents the residue Cys with the α-helix structure. Most of the substitution scores are positive if two RS letters in the same secondary structure are aligned. On the other hand, the lowest substitution score is -7.8 in this S2A2. All of the substitution scores are low when the helix RS letters are aligned with the strand RS letters. The above relationships are in good agreement with biological functions of the relevant structures, showing that the matrix S2A2 embodies conventional knowledge about secondary structure conservation in proteins.
We compared the S2A2 matrix with BLOSUM62. The highest substitution scores are 6.2 (S2A2) and 11 (BLOSUM62). In contrast, the lowest score for S2A2 (-7.8) is much lower than that for BLOSUM62 (-4). The main reasons for this large difference are that α-helices and β-strands constitute very different protein secondary structures, and the RS letters pertaining to these two types of structure are more conserved than amino acid sequences. These results demonstrate that the RS letters with the S2A2 matrix may be able to more accurately find remote homologous sequences than simple amino acid sequence analyses.
Comparing S2A2 matrix with other methods for fold recognition on the Lindahl benchmark
Comparing S2A2 matrix with other methods for sequence alignment accuracies on the ProSup benchmark
S2A2 + PSSMa
CASP8 structure prediction
Our previous server ((PS)2-CASP8) and other 70 servers participated in the CASP8 competition, involving 121 targets for tertiary structure prediction. These 121 targets are officially classified into 154 TBM domains (Table S1 in Additional file 3). The accuracies of these 71 servers were evaluated based on the GDT_TS  scores directly summarized from the CASP8 website http://predictioncenter.org/casp8/.
(PS)2-v2, (PS)2-original and (PS)2-CASP8 servers were evaluated on these 154 TBM targets (Figure 4, Table 4 and Table S2 in Additional file 4). The sum of GDT_TS scores were 10331.4 ((PS)2-v2), 9954.4 ((PS)2-CASP8) and 9447.5 ((PS)2-original), respectively. (PS)2-v2 yielded 99 and 34 higher GDT_TS scores than (PS)2-original and (PS)2-CASP8, respectively, among 154 targets. When the sequence identity between the target and template was more than 30%, these three servers achieved similar GDT_TS scores. However, if the sequence identity was less than 20%, the (PS)2-v2 server was significantly better than (PS)2-original server (p-value is 4.0E-7) and (PS)2-CASP8 (p-value is 6.6E-4) using the paired Student's t-test (Table 4). For each target in CASP8, Table S2 (in Additional file 4) shows the GDT_TS score improvement with contributing components (i.e. multiple templates, multiple models, and template search method) between the (PS)2-v2 and our previous servers.
These 154 TBM targets were also used to evaluate the automatic servers participating in CASP8. For the templates selection, the accuracy of identifying the best template of the target protein was used to evaluate the performance of these servers (Figure S2 in Additional file 5). The accuracies of the (PS)2-v2 server were 54.1% and 75.0% for identifying the Top 1 templates and Top 10 templates, respectively. In addition, (PS)2-v2 was the rank 6th among these 72 severs based on GDT_TS scores (Table 5). This server is often able to yield reliable predicted structures (i.e. GDT_TS score = 60%) if the E-value is less than 10-2 (Figure S3 in Additional file 6).
Comparison the (PS)2-v2 server with (PS)2-original and (PS)2-CASP8 servers on the 154 TBM targets in CASP8 based on GDT_TS scores
SIa ≥ 30% (nb = 40)
20% ≤ SI < 30% (n= 47)
SI < 20% (n= 67)
Comparing (PS)2-v2 with 71 automatic servers on 154 targets in CASP8
Sum of GDT_TS score
10469.3 ~ 10452.9
BAKER-ROBETTA, (PS) 2 -v2, MULTICOM-CLUSTER
10358.9, 10331.4, 10325.8
Multiple templates for multiple domains
Multiple models and model selection
Figure 6 shows the improvement in GDT_TS scores of (PS)2-v2 by applying a multiple-model strategy and using the program ProQ for the final model selection. Among these 154 CASP8 targets, (PS)2-v2 improved GDT_TS scores for 23 targets; conversely, only 4 targets are lightly worse when (PS)2-v2 used a multiple-model strategy. For the other 127 targets, (PS)2-v2 obtained the same GDT_TS scores and the total GDT_TS improvement is 145.3. According to the paired Student's t-test (p-value is 0.0045 shown in Table S4 Additional file 8), (PS)2-v2 applying the multiple-model strategy significantly improved the GDT_TS scores when the sequence identity between the target and the template is less than 20%.
T0409 in CASP8
The target T0409 selected from CASP8 was taken to describe the structure modeling of the (PS)2-v2 server (Figure 8). The target is the BIG_1156.2 domain of putative penicillin-binding protein MrcA from Nitrosomonas europaea ATCC 19718. This server yielded the best GDT_TS score (77.8) among all participating servers for this target.
This study presents an automatic server for protein structure predictions by applying numerous enhancements and modifications to the original technique, thereby improving the reliability and applicability. By integrating the S2A2 and PSSM matrixes, the (PS)2-v2 server seamlessly blends the amino acid and structural propensities so that they work cooperatively for the template selection and target-template alignments. In addition, our (PS)2-v2 utilizes multiple templates and multiple models for building models and assessing models. Experimental results demonstrate that the (PS)2-v2 server is efficient and effective for template selections and target-template alignments in template-based modeling. We believe that this server is useful in protein structure prediction and modeling, especially in detecting homologous templates with sequence similarity in the twilight zone.
Project home page: http://ps2v2.life.nctu.edu.tw
Operating system(s): Platform independent
Programming language: C, Perl and PHP
Any restrictions to use by non-academics: None
J.-M. Yang was supported by National Science Council and partial support of the ATU plan by MOE. Authors are grateful to both the hardware and software supports of the Structural Bioinformatics Core Facility at National Chiao Tung University.
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