Gaussian Accelerated Molecular Dynamics in GROMACS

Abstract

Gaussian accelerated molecular dynamics (GaMD) enhances conformational sampling by adding a smooth boost potential without requiring predefined collective variables, but an engine-integrated implementation has not been available in GROMACS. Here, we implement total-, dihedral-, and dual-boost GaMD in GROMACS 2025.4, including staged energy-statistics collection, GPU-based bias evaluation and force scaling, restart support, and outputs required for cumulant-based free-energy reweighting. The implementation was evaluated using four benchmark systems spanning conformational free energies, protein folding, and ligand recognition. For alanine dipeptide, a reweighted 100 ns GaMD trajectory recovered the major free-energy basins and rotational barriers in overall agreement with a 1000 ns conventional MD simulation. For chignolin and TC5b, all three independent trajectories for each system sampled native-like folded states from extended conformations within 300 ns and 1 μs, respectively; the best TC5b structure had a minimum backbone RMSD of 0.03 nm from the experimental structure. In the benzene–T4 lysozyme system, two of five independent 500 ns trajectories captured both ligand binding and dissociation, yielding a bound pose with a minimum ligand RMSD of 0.06 nm from the crystal structure. Across all four systems, the boost-potential distributions were approximately Gaussian, and second-order cumulant reweighting resolved the expected conformational and binding free-energy basins. These results demonstrate that GROMACS-GaMD provides a practical, GPU-enabled, collective-variable-free enhanced-sampling framework for biomolecular free-energy calculations, protein folding, and ligand-binding studies.