Fold classification based on secondary structure--how much is gained by including loop topology?

Abstract

Background: It has been proposed that secondary structure information can be used to classify (to some extend) protein folds. Since this method utilizes very limited information about the protein structure, it is not surprising that it has a higher error rate than the approaches that use full 3D fold description. On the other hand, the comparing of 3D protein structures is computing intensive. This raises the question to what extend the error rate can be decreased with each new source of information, especially if the new information can still be used with simple alignment algorithms. We consider the question whether the information about closed loops can improve the accuracy of this approach. While the answer appears to be obvious, we had to overcome two challenges. First, how to code and to compare topological information in such a way that local alignment of strings will properly identify similar structures. Second, how to properly measure the effect of new information in a large data sample. We investigate alternative ways of computing and presenting this information.

Results: We used the set of beta proteins with at most 30% pairwise identity to test the approach; local alignment scores were used to build a tree of clusters which was evaluated using a new log-odd cluster scoring function. In particular, we derive a closed formula for the probability of obtaining a given score by chance. Parameters of local alignment function were optimized using a genetic algorithm. Of 81 folds that had more than one representative in our data set, log-odds scores registered significantly better clustering in 27 cases and significantly worse in 6 cases, and small differences in the remaining cases. Various notions of the significant change or average change were considered and tried, and the results were all pointing in the same direction.

Conclusion: We found that, on average, properly presented information about the loop topology improves noticeably the accuracy of the method but the benefits vary between fold families as measured by log-odds cluster score.

Figure 1

Sums of average unweighted log-odds scores with weighted log-odds scores for different values of L. The value for L = 0 corresponds to NCL.

Figure 2

Ideal cases of a parallel and anti-parallel beta sheets. Residue numbers are surrounded by the backbone atoms of the respective residue, differences of hydrogen bonds are positioned next to the respective bonds and second differences are placed in boxes.