Wang, J.; Miao, Y.

Binding thermodynamics and kinetics play critical roles in drug design. However, it has proven challenging to efficiently predict ligand binding thermodynamics and kinetics of small molecules and flexible peptides using conventional Molecular Dynamics (cMD), due to limited simulation timescales. Based on our previously developed Ligand Gaussian accelerated Molecular Dynamics (LiGaMD) method, we present a new approach, termed LiGaMD3, in which we introduce triple boosts into three individual energy terms that play important roles in small-molecule/peptide dissociation, rebinding and system conformational changes to improve the sampling efficiency of small-molecule/peptide interactions with target proteins. To validate the performance of LiGaMD3, MDM2 bound by a small molecule (Nutlin 3) and two highly flexible peptides (PMI and P53) were chosen as model systems. LiGaMD3 could efficiently capture repetitive small-molecule/peptide dissociation and binding events within 2 microsecond simulations. The predicted binding kinetic constant rates and free energies from LiGaMD3 agreed with available experimental values and previous simulation results. Therefore, LiGaMD3 provides a more general and efficient approach to capture dissociation and binding of both small-molecule ligand and flexible peptides, allowing for accurate prediction of their binding thermodynamics and kinetics.