I-TASSER: fully automated protein structure prediction in CASP8

Abstract

The I-TASSER algorithm for 3D protein 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 the human predictions incorporate more diverse templates from other servers which improve the human predictions in some of the distant homology targets. 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 accuracy of the sequence based contact predictions is on average 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 in 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.

Figure 1

Comparison of the best threading templates with the first model predicted by the I-TASSER server. RMSD for models is calculated in the same aligned region as the threading template. The highlights in (b) are two domains where I-TASSER deteriorates the best templates.

Figure 2

The procedure of the I-TASSER server in modeling a FM target of T0416_2. The upper part shows the top 20 alignments by LOMETS for the whole-chain sequence followed by the subsequent threading on the domain which was missed in the whole-chain threading. The examples of 4 templates closest to the target are shown in the third row. The fourth row shows the native backbone structure with inter-residue lines indicating the side-chain contact predictions by SVMSEQ (red solid lines are true-positive and green dashed lines are false-positive predictions). The domain modeling was done in the sequence (L112-T198) but the tails (L112-E125 and F192-T198 shown as backbones in the final models) are trimmed during docking with other parts of the structures. The superposition is made on S124-K180 according to the assessor’s definition of T0416_2. The image is generated by MVP.

Figure 3

SVMSEQ contact predictions improve the modeling of T0437_1. (a) Structural superposition of the target (thin backbone) on the best template 2jz5A (thick backbone) with structural alignment generated by TM-align (RMSD =1.34A, TM-score =0.838). (b) Backbone structure of the native with lines between residues indicating Cα contact prediction from LOMETS. Red solid lines are true-positive and green dashed ones are false-positive. There is no true-positive contact in the lower part of the second beta-hairpin. (c) Same as (b) but contacts are from SVMSEQ with 10 true-positive predictions in the lower part of the second beta-hairpin. (d) Superposition of the I-TASSER server model on the native with a RMSD =1.13 A and a TM-score=0.885. The image is generated by MVP.

Figure 4

Comparison of the first models predicted by human (as “Zhang”) and server (as “Zhang-Server”) for all 164 domains.

Figure 5

TM-score of the I-TASSER server prediction (stars) in control with the best model (solid spheres) predicted by other servers in CASP8. (a) The first model by I-TASSER. (b) The best in top 100 models in I-TASSER simulation.

Figure 6

Structural modeling for T0504. (a) The experimental structure of the first two domains of T0504. (b) The template structure of 2gf7A detected by LOMETS which has the beta-hairpin swapped and may reflect a new evolution mechanism from the target. (c) Superposition of the native on the I-TASSER model (white backbone). The native structures of T0504_1 and T0504_2 are in blue and red. The architecture of the model and the native is similar but with different orientation of beta-hairpins.

Figure 7

The I-TASSER modeling for T0405_1 (a), where the mirror image structure (c) is ranked higher than the correct model (b).