Abstract
Calculations of ligand binding free energies and kinetic rates are important for drug design. However, such tasks have proven challenging in computational chemistry and biophysics. To address this challenge, we have developed a new computational method, ligand Gaussian accelerated molecular dynamics (LiGaMD), which selectively boosts the ligand nonbonded interaction potential energy based on the Gaussian accelerated molecular dynamics (GaMD) enhanced sampling technique. Another boost potential could be applied to the remaining potential energy of the entire system in a dual-boost algorithm (LiGaMD_Dual) to facilitate ligand binding. LiGaMD has been demonstrated on host-guest and protein-ligand binding model systems. Repetitive guest binding and unbinding in the β-cyclodextrin host were observed in hundreds-of-nanosecond LiGaMD_Dual simulations. The calculated guest binding free energies agreed excellently with experimental data with <1.0 kcal/mol errors. Compared with converged microsecond-time scale conventional molecular dynamics simulations, the sampling errors of LiGaMD_Dual simulations were also <1.0 kcal/mol. Accelerations of ligand kinetic rate constants in LiGaMD simulations were properly estimated using Kramers' rate theory. Furthermore, LiGaMD allowed us to capture repetitive dissociation and binding of the benzamidine inhibitor in trypsin within 1 μs simulations. The calculated ligand binding free energy and kinetic rate constants compared well with the experimental data. In summary, LiGaMD provides a powerful enhanced sampling approach for characterizing ligand binding thermodynamics and kinetics simultaneously, which is expected to facilitate computer-aided drug design.