PackDock is a Flexible Protein-Ligand Docking Approach with Diffusion-Based Side Chain Packing

Abstract Understanding protein structure and dynamics is crucial for basic biology and drug design. Conventional methods often provide static conformations that inadequately capture protein flexibility. We present PackDock, a novel approach combining "conformation selection" and "induced fit" mechanisms to model protein-ligand interactions. PackDock's core, PackPocket, uses a diffusion model to sample diverse binding pocket conformations or predict ligand-induced changes. We validate PackDock through side-chain packing, re-docking, and cross-docking experiments, demonstrating its ability to address protein flexibility challenges. In a real-world application, PackDock identified nanomolar affinity compounds with new scaffolds. Additionally, it revealed key amino acid conformational changes, offering insights into protein-ligand interactions. By accurately predicting complex conformations in various scenarios, PackDock enhances our understanding of protein dynamics and provides new perspectives for both basic biological research and drug discovery efforts.