Prediction of homology model quality with multivariate regression.

Abstract

A new method has been developed for prediction of homology model quality directly from the sequence alignment, using multivariate regression. Hence, the expected quality of future homology models can be estimated using only information about the primary structure. This method has been applied to protein kinases and can easily be extended to other protein families. Homology model quality for a reference set of homology models was verified by comparison to experimental structures, by calculation of root-mean-square deviations (RMSDs) and comparison of interresidue contact areas. The homology model quality measures were then used as dependent variables in a Partial Least Squares (PLS) regression, using a matrix of alignment score profiles found from the Point Accepted Mutation (PAM) 250 similarity matrix as independent variables. This resulted in a regression model that can be used to predict the accuracy of future homology models from the sequence alignment. Using this method, one can identify the target-template combinations that are most likely to give homology models of sufficient quality. Hence, this method can be used to effectively choose the optimal templates to use for the homology modeling. The method's ability to guide the choice of homology modeling templates was verified by comparison of success rates to those obtained using BLAST scores and target-template sequence identities, respectively. The results indicate that the method presented here performs best in choosing the optimal homology modeling templates. Using this method, the optimal template was chosen in 86% of the cases, as compared to 62% using BLAST scores, and 57% using sequence identities. The method presented here can also be used to identify regions of the protein structure that are difficult to model, as well as alignment errors. Hence, this method is a useful tool for ensuring that the best possible homology model is generated.