RAMD

RAMD accelerates ligand unbinding in molecular dynamics simulations to explore ligand dissociation mechanisms and quantify unbinding kinetics using interaction fingerprint analysis.

Key Features:

• Enhanced sampling: Applies a randomly oriented external acceleration to ligands to accelerate unbinding and sample ligand egress routes without prior reaction-coordinate definition.
• τRAMD procedure: Computes relative residence times of ligands to provide comparative unbinding kinetics.
• Integration with machine learning: Combines RAMD with machine-learning analysis of protein-ligand interaction fingerprints (IFPs) to identify molecular features that influence ligand unbinding kinetics.
• GROMACS 2020 implementation: Implements RAMD within GROMACS 2020 to enable scalable execution on large molecular systems.
• MD-IFP tools: Generates interaction fingerprints along unbinding trajectories and maps dissociation trajectories onto IFP space to characterize dissociation routes and metastable states.

Scientific Applications:

• Exploration of ligand egress routes: Maps ligand dissociation trajectories to identify egress pathways from macromolecular binding sites.
• Quantification of unbinding kinetics: Provides comparative estimates of ligand residence times and unbinding kinetics using τRAMD.
• Identification of molecular determinants: Uses ML on protein-ligand IFPs to reveal molecular features and interactions that modulate unbinding kinetics and metastable states.
• Support for drug design: Supplies mechanistic insight into ligand unbinding to inform optimization of pharmaceutical inhibitors.

Methodology:

Computational methods explicitly include applying a randomly oriented external acceleration during MD for enhanced sampling, the τRAMD procedure to compute relative residence times, machine-learning analysis of protein-ligand interaction fingerprints (IFPs), implementation in GROMACS 2020, and MD-IFP generation and mapping of IFPs along unbinding trajectories to characterize dissociation routes and metastable states.