Ligand Gaussian Accelerated Molecular Dynamics 3 (LiGaMD3): Improved Calculations of Binding Thermodynamics and Kinetics of Both Small Molecules and Flexible Peptides

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 time scales. 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 the
model systems. LiGaMD3 could efficiently capture repetitive small-molecule/peptide
dissociation and binding events within 2 μs simulations. The
predicted binding kinetic constant rates and free energies from LiGaMD3
were in agreement with the 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
ligands and flexible peptides, allowing for accurate prediction of
their binding thermodynamics and kinetics.