Accurate Determination of Host–Guest Standard Binding Free Energies and Kinetic Parameters from Replica Exchange Molecular Dynamics Simulation

Accurate prediction of drug kinetic rates is critical for rational drug design, especially since the drug residence time has been shown to correlate strongly with its efficacy. Molecular dynamics (MD) simulations are widely used to investigate ligand binding and dissociation processes. However, due to the time scale limitation, capturing ligand dissociation events remain a major challenge for MD simulations. Enhanced sampling techniques can provide the potential of mean force (PMF) for the dissociation process, but their modified dynamics often prevent reliable estimation of dissociation rates and mechanistic details. Here, we present a proof-of-principle study that combines replica exchange molecular dynamics (REMD) with Kramers' rate theory, enabling not only the sampling of equilibrium properties but also the extraction of kinetic information on ligand binding kinetics on host-guest systems. The calculated standard binding free energies agreed excellently with experimental data with <0.8 kcal/mol errors for the host-guest systems. Furthermore, the calculated kinetic rate constants compared well with the experimental data within errors less than an order of magnitude. In summary, this work establishes an efficient and reliable approach to characterize both ligand binding thermodynamics and kinetics using well-defined model systems, offering a validated foundation for future extension to complex biomolecular systems.