Fr-TM-align: a new protein structural alignment method based on fragment alignments and the TM-score

Abstract

Background: Protein tertiary structure comparisons are employed in various fields of contemporary structural biology. Most structure comparison methods involve generation of an initial seed alignment, which is extended and/or refined to provide the best structural superposition between a pair of protein structures as assessed by a structure comparison metric. One such metric, the TM-score, was recently introduced to provide a combined structure quality measure of the coordinate root mean square deviation between a pair of structures and coverage. Using the TM-score, the TM-align structure alignment algorithm was developed that was often found to have better accuracy and coverage than the most commonly used structural alignment programs; however, there were a number of situations when this was not true.

Results: To further improve structure alignment quality, the Fr-TM-align algorithm has been developed where aligned fragment pairs are used to generate the initial seed alignments that are then refined using dynamic programming to maximize the TM-score. For the assessment of the structural alignment quality from Fr-TM-align in comparison to other programs such as CE and TM-align, we examined various alignment quality assessment scores such as PSI and TM-score. The assessment showed that the structural alignment quality from Fr-TM-align is better in comparison to both CE and TM-align. On average, the structural alignments generated using Fr-TM-align have a higher TM-score (~9%) and coverage (~7%) in comparison to those generated by TM-align. Fr-TM-align uses an exhaustive procedure to generate initial seed alignments. Hence, the algorithm is computationally more expensive than TM-align.

Conclusion: Fr-TM-align, a new algorithm that employs fragment alignment and assembly provides better structural alignments in comparison to TM-align. The source code and executables of Fr-TM-align are freely downloadable at: http://cssb.biology.gatech.edu/skolnick/files/FrTMalign/.

Figure 1

A) Difference in TM-score from Fr-TM-align and TM-align plotted against the TM-score from TM-align for dataset 1. B) Similar data as in A, but plotted for dataset 2. (dTM is defined as (TM-score (Fr-TM-align) – TM-score (TM-align)).

Figure 2

A) Scatter plot showing the number of aligned residues from Fr-TM-align versus the number of aligned residues from TM-align for dataset 1. B) Similar data as in A, but plotted for dataset 2.

Figure 3

A) Histogram showing the fraction of protein pairs in various PSI (in %) bins for the dataset 1. B) Similar data as in A, but plotted for dataset 2.

Figure 4

Histogram showing the fraction of protein pairs with improved/decreased or unchanged TM-score by Fr-TM-align with respect to the TM-score reported by TM-align. dTM is defined as (TM-score (Fr-TM-align) – TM-score (TM-align)).

Figure 5

Histogram showing the fraction of protein pairs with improved/decreased or without any change in TM-score by Fr-TM-align with respect to the length of the smaller protein of the two proteins being aligned. dTM is defined as (TM-score (FrTMalign) – TM-score (TM-align)).

Figure 6

Two examples showing the structural alignments from Fr-TM-align and TM-align. A) The structural alignment between 2GZQ_A (186 residues) and 1A1M_B (99 residues). B) The structural alignment between 1AOL (228 residues) and 1AKP (114 residues). The first row shows the ribbon diagrams of the native structures. The beta-sheets in the native structures are colored in cyan to highlight the structurally similar region, while the remainder of the structure is transparent gray. The second row is the structural alignment given by TM-align and Fr-TM-align. L denotes the number of aligned residues. The longer of the two proteins is shown in light green color and the smaller protein is shown in light yellow color. The aligned (unaligned) regions are shown in the thick backbone (thin) backbone.