BLUES

BLUES applies nonequilibrium candidate Monte Carlo (NCMC) to enhance sampling of protein-ligand binding modes and improve prediction of binding affinities, particularly for rigid fragment-like ligands.

Key Features:

• Nonequilibrium Candidate Monte Carlo (NCMC): Employs NCMC to rotate ligands within a receptor environment and allow them to relax through alchemical perturbation evaluated as a nonequilibrium Monte Carlo move.
• Alchemical perturbation and relaxation: Uses alchemical perturbation during relaxation phases to enable exploration of alternative ligand poses and conformations.
• Enhanced sampling efficiency: Demonstrates sampling improvements of over two orders of magnitude compared to brute-force molecular dynamics simulations.
• Rapid decorrelation of binding modes: Facilitates rapid decorrelation of ligand binding modes through nonequilibrium Monte Carlo moves.
• Application to rigid fragments: Targets prediction of dominant placement, conformation, and orientations of rigid, fragment-like ligands within receptors.

Scientific Applications:

• Prediction of binding affinities and modes: Improves sampling needed for accurate prediction of protein-ligand binding affinities and binding modes.
• Alchemical free energy calculations: Supports alchemical calculations used to predict ligand binding free energies by improving sampling of relevant binding modes.
• Fragment-based drug design: Addresses sampling challenges relevant to fragment-based drug discovery and development.

Methodology:

Performs ligand rotations followed by relaxation via alchemical perturbation, evaluates these perturbations as nonequilibrium Monte Carlo moves (NCMC), and the approach was tested on a T4 lysozyme model binding system.