Improving prediction of protein secondary structure using structured neural networks and multiple sequence alignments.

The prediction of protein secondary structure by use of carefully structured neural networks and multiple sequence alignments has been investigated. Separate networks are used for predicting the three secondary structures alpha-helix, beta-strand, and coil. The networks are designed using a priori knowledge of amino acid properties with respect to the secondary structure and the characteristic periodicity in alpha-helices. Since these single-structure networks all have less than 600 adjustable weights, overfitting is avoided. To obtain a three-state prediction of alpha-helix, beta-strand, or coil, ensembles of single-structure networks are combined with another neural network. This method gives an overall prediction accuracy of 66.3% when using 7-fold cross-validation on a database of 126 nonhomologous globular proteins. Applying the method to multiple sequence alignments of homologous proteins increases the prediction accuracy significantly to 71.3% with corresponding Matthew's correlation coefficients C alpha = 0.59, C beta = 0.52, and Cc = 0.50. More than 72% of the residues in the database are predicted with an accuracy of 80%. It is shown that the network outputs can be interpreted as estimated probabilities of correct prediction, and, therefore, these numbers indicate which residues are predicted with high confidence.