MetaScore: A Novel Machine-Learning-Based Approach to Improve Traditional Scoring Functions for Scoring Protein-Protein Docking Conformations

Protein-protein interactions play a ubiquitous role in biological function. Knowledge of the three-dimensional (3D) structures of the complexes they form is essential for understanding the structural basis of those interactions and how they orchestrate key cellular processes. Computational docking has become an indispensable alternative to the expensive and time-consuming experimental approaches for determining the 3D structures of protein complexes. Despite recent progress, identifying near-native models from a large set of conformations sampled by docking-the so-called scoring problem-still has considerable room for improvement. We present MetaScore, a new machine-learning-based approach to improve the scoring of docked conformations. MetaScore utilizes a random forest (RF) classifier trained to distinguish near-native from non-native conformations using their protein-protein interfacial features. The features include physicochemical properties, energy terms, interaction-propensity-based features, geometric properties, interface topology features, evolutionary conservation, and also scores produced by traditional scoring functions (SFs). MetaScore scores docked conformations by simply averaging the score produced by the RF classifier with that produced by any traditional SF. We demonstrate that (i) MetaScore consistently outperforms each of the nine traditional SFs included in this work in terms of success rate and hit rate evaluated over conformations ranked among the top 10; (ii) an ensemble method, MetaScore-Ensemble, that combines 10 variants of MetaScore obtained by combining the RF score with each of the traditional SFs outperforms each of the MetaScore variants. We conclude that the performance of traditional SFs can be improved upon by using machine learning to judiciously leverage protein-protein interfacial features and by using ensemble methods to combine multiple scoring functions.

Automated summary

Protein-protein interactions are crucial for biological function, and understanding their three-dimensional structures is essential. Computational docking is a useful alternative to experimental approaches for determining these structures, but the scoring problem still needs improvement. MetaScore is a machine-learning-based approach that uses protein-protein interfacial features to score docked conformations. It consistently outperforms traditional scoring functions and an ensemble method combining MetaScore with traditional functions achieves even better performance. Machine learning and ensemble methods can improve the accuracy of scoring protein-protein interactions.