Improving the quality of protein structure models by selecting from alignment alternatives

The approach has been tested on a representative set of proteins. The ability of the method to improve models was validated by comparing the MQAP-selected structures to the native structures with the model quality evaluation program TM-score. Using the SVM-based model selection, a significant increase in model quality is obtained (as shown with a Wilcoxon signed rank test yielding p-values below 10-15). The average increase in TMscore is 0.016, the maximum observed increase in TM-score is 0.29.In template-based protein structure prediction alignment is known to be a bottleneck limiting the overall model quality. Here we show that a combination of systematic alignment variation and modern model scoring functions can significantly improve the quality of alignment-based models.Protein structure prediction by comparative modeling and/or fold recognition consists of three largely independent steps: (1) Postulating the structural similarity of the target protein sequence with a known template structure on the basis of a significant alignment score between the two protein sequences. (2) This or a different alignment serves as a basis for model construction. In this process residues in the target sequence that are aligned to residues in the template structure are mapped on the corresponding coordinates in the structure. (3) Finally, unmapped regions are filled in, breaks in the backbone are mended, and the overall model is refined.Thus the quality of the alignment in the second step has an essential impact on the quality of the resulting model. The continual benchmarks in the biannual CASP assessment of protein structure prediction methods witness that there is significant progress in identifying suitable templates [1], due in part to the introduction of profile-profile alignment methods [2-5] and the sophisticated construction of profiles [6]. While CASP assessors found little improvement in the predicted models [7], they found steady progress in alignment quality over the