Systematic assessment of accuracy of comparative model of proteins belonging to different structural fold classes.

In the absence of experimental structures, comparative modeling continues to be the chosen method for retrieving structural information on target proteins. However, models lack the accuracy of experimental structures. Alignment error and structural divergence (between target and template) influence model accuracy the most. Here, we examine the potential additional impact of backbone geometry, as our previous studies have suggested that the structural class (all-α, αβ, all-β) of a protein may influence the accuracy of its model. In the twilight zone (sequence identity ≤ 30%) and at a similar level of target-template divergence, the accuracy of protein models does indeed follow the trend all-α > αβ > all-β. This is mainly because the alignment accuracy follows the same trend (all-α > αβ > all-β), with backbone geometry playing only a minor role. Differences in the diversity of sequences belonging to different structural classes leads to the observed accuracy differences, thus enabling the accuracy of alignments/models to be estimated a priori in a class-dependent manner. This study provides a systematic description of and quantifies the structural class-dependent effect in comparative modeling. The study also suggests that datasets for large-scale sequence/structure analyses should have equal representations of different structural classes to avoid class-dependent bias.