Pre-training of Equivariant Graph Matching Networks with Conformation Flexibility for Drug Binding

The latest biological findings observe that the traditional motionless 'lock-and-key' theory is not generally applicable because the receptor and ligand are constantly moving. Nonetheless, remarkable changes in associated atomic sites and binding pose can provide vital information in understanding the process of drug binding. Based on this mechanism, molecular dynamics (MD) simulations were invented as a useful tool for investigating the dynamic properties of a molecular system. However, the computational expenditure limits the growth and application of protein trajectory-related studies, thus hindering the possibility of supervised learning. To tackle this obstacle, we present a novel spatial-temporal pre-training method based on the modified Equivariant Graph Matching Networks (EGMN), dubbed ProtMD, which has two specially designed self-supervised learning tasks: an atom-level prompt-based denoising generative task and a conformation-level snapshot ordering task to seize the flexibility information inside MD trajectories with very fine temporal resolutions. The ProtMD can grant the encoder network the capacity to capture the time-dependent geometric mobility of conformations along MD trajectories. Two downstream tasks are chosen, i.e., the binding affinity prediction and the ligand efficacy prediction, to verify the effectiveness of ProtMD through linear detection and task-specific fine-tuning. We observe a huge improvement from current state-of-the-art methods, with a decrease of 4.3\% in RMSE for the binding affinity problem and an average increase of 13.8\% in AUROC and AUPRC for the ligand efficacy problem. The results demonstrate valuable insight into a strong correlation between the magnitude of conformation's motion in the 3D space (i.e., flexibility) and the strength with which the ligand binds with its receptor.