ct0c00395_si_002.mp4 (3.71 MB)
Ligand Gaussian Accelerated Molecular Dynamics (LiGaMD): Characterization of Ligand Binding Thermodynamics and Kinetics
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posted on 2020-08-07, 12:05 authored by Yinglong Miao, Apurba Bhattarai, Jinan WangCalculations 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.