A multi-grained symmetric differential equation model for learning protein-ligand binding dynamics

Journal article

Molecular dynamics (MD) simulation is a key tool in drug discovery for predicting protein-ligand binding affinities, transport properties, and pocket dynamics. While advances in numerical and machine learning (ML) methods have improved MD efficiency, accurately modeling long-timescale dynamics remains challenging. We introduce NeuralMD, an ML surrogate that accelerates and enhances MD simulations of protein-ligand binding. NeuralMD employs a physics-informed, multi-grained, group-symmetric framework comprising (1) BindingNet, which enforces symmetry via vector frames and captures multi-level protein-ligand interactions, and (2) an augmented neural differential equation solver that learns trajectories under Newtonian mechanics. Across ten single-trajectory and three multi-trajectory tasks, NeuralMD achieves up to 15 × lower reconstruction error and 70% higher validity than existing ML baselines. The predicted oscillations closely align with ground-truth dynamics, establishing NeuralMD as a foundation for next-generation protein-ligand simulation research.

Authors: Liu, S; Du, W; Xu, H; Li, Y; Li, Z

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 17
• Issue: 1
• Article number: 1049
• Publication date: 2025-12-30
• Acceptance date: 2025-12-05
• DOI: 10.1038/s41467-025-67808-z
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: Solver; Symmetry (geometry); Dynamics (music); Ordinary differential equation; Key (lock); Differential equation