A-RFP: An Adaptive Residue Flexibility Prediction Method Improving Protein-ligand Docking Based on Homologous Proteins

Background:Computational molecular docking plays an important role in determining the precise receptor-ligand conformation, which becomes a powerful tool for drug discovery. In the past 30 years, most computational docking methods have treated the receptor structure as a rigid body, although flexible docking often yields higher accuracy. The main disadvantage of flexible docking is its significantly higher computational cost. Due to the fact that different protein pocket residues exhibit different degrees of flexibility, semi-flexible docking methods, balancing rigid docking and flexible docking, have demonstrated success in predicting highly accurate conformations with a relatively low computational cost.

Methods:In our study, the number of flexible pocket residues was assessed by quantitative analysis, and a novel adaptive residue flexibility prediction method, named A-RFP, was proposed to improve the docking performance. Based on the homologous information, a joint strategy is used to predict the pocket residue flexibility by combining RMSD, the distance between the residue sidechain and the ligand, and the sidechain orientation. For each receptor-ligand pair, A-RFP provides a docking conformation with the optimal affinity.

Results:By analyzing the docking affinities of 3507 target-ligand pairs in 5 different values ranging from 0 to 10, we found there is a general trend that the larger number of flexible residues inevitably improves the docking results by using Autodock Vina. However, a certain number of counterexamples still exist. To validate the effectiveness of A-RFP, the experimental assessment was tested in a small-scale virtual screening on 5 proteins, which confirmed that A-RFP could enhance the docking performance. And the flexible-receptor virtual screening on a low-similarity dataset with 85 receptors validates the accuracy of residue flexibility comprehensive evaluation. Moreover, we studied three receptors with FDA-approved drugs, which further proved A-RFP can play a suitable role in ligand discovery.

Conclusion:Our analysis confirms that the screening performance of the various numbers of flexible residues varies wildly across receptors. It suggests that a fine-grained docking method would offset the aforementioned deficiency. Thus, we presented A-RFP, an adaptive pocket residue flexibility prediction method based on homologous information. Without considering computational resources and time costs, A-RFP provides the optimal docking result.