Prediction of flexible/rigid regions from protein sequences using k-spaced amino acid pairs

Traditionally, it is believed that the native structure of a protein corresponds to a global minimum of its free energy. However, with the growing number of known tertiary (3D) protein structures, researchers have discovered that some proteins can alter their structures in response to a change in their surroundings or with the help of other proteins or ligands. Such structural shifts play a crucial role with respect to the protein function. To this end, we propose a machine learning method for the prediction of the flexible/rigid regions of proteins (referred to as FlexRP); the method is based on a novel sequence representation and feature selection. Knowledge of the flexible/rigid regions may provide insights into the protein folding process and the 3D structure prediction.

The flexible/rigid regions were defined based on a dataset, which includes protein sequences that have multiple experimental structures, and which was previously used to study the structural conservation of proteins. Sequences drawn from this dataset were represented based on feature sets that were proposed in prior research, such as PSI-BLAST profiles, composition vector and binary sequence encoding, and a newly proposed representation based on frequencies of k-spaced amino acid pairs. These representations were processed by feature selection to reduce the dimensionality. Several machine learning methods for the prediction of flexible/rigid regions and two recently proposed methods for the prediction of conformational changes and unstructured regions were compared with the proposed method. The FlexRP method, which applies Logistic Regression and collocation-based representation with 95 features, obtained 79.5% accuracy. The two runner-up methods, which apply the same sequence representation and Support Vector Machines (SVM) and Naïve Bayes classifiers, obtained 79.2% and 78.4% accuracy, respectively. The remaining considered methods are characterized by accuracies below 70%. Finally, the Naïve Bayes method is shown to provide the highest sensitivity for the prediction of flexible regions, while FlexRP and SVM give the highest sensitivity for rigid regions.

A new sequence representation that uses k-spaced amino acid pairs is shown to be the most efficient in the prediction of the flexible/rigid regions of protein sequences. The proposed FlexRP method provides the highest prediction accuracy of about 80%. The experimental tests show that the FlexRP and SVM methods achieved high overall accuracy and the highest sensitivity for rigid regions, while the best quality of the predictions for flexible regions is achieved by the Naïve Bayes method.