Global Optimization of the Lennard-Jones Parameters for the Drude Polarizable Force Field

Molecular dynamics (MD) simulations
based on atomic models play
an important role in the drug-discovery process to screen molecules,
estimate binding free energies, and optimize lead compounds in chemical
space. Accurate computations of thermodynamic and kinetic properties
using MD simulations are highly dependent on the accuracy of the underlying
atomic force field. In this context, going beyond the nonpolarizable
fixed-charge model by accounting explicitly for induced polarization
is highly desirable. The CHARMM polarizable force field based on classical
Drude oscillators, in which an auxiliary charged particle is attached
via a harmonic spring to its parent nucleus, offers both a computationally
convenient and rigorous framework to model explicitly induced electronic
polarization in MD simulations. For any molecule of interest, electrostatic
partial charges, atomic polarizabilities, and Thole shielding factors,
as well as bonded parameters can either be determined from ab initio
calculations or ascribed from the knowledge-based library of the CHARMM
Generalized force field. While this approach is fairly reliable in
general, it is well understood that the overall accuracy of the models
with respect to thermodynamic properties such as bulk density, enthalpies,
and solvation free energies is particularly sensitive to the nonbonded
Lennard-Jones (LJ) parameters. In the present study, we systematically
refined the set of LJ parameters for the atom types available in the
Drude force field to best match the experimental thermodynamic properties
for 416 small druglike organic molecules. To further test the transferability
of the optimized parameters, the hydration free energy of 372 molecules
was computed. The calculations resulted in a small average error of
0.46 kcal/mol and a Pearson R of 0.9, representing
a significant improvement over the additive GAFF force field in our
previous study, where an average error of ∼2 kcal/mol was obtained.
Such an improvement is consistent with the ability of the polarizable
Drude model to more accurately model interactions in different environments.
The effort provides a roadmap for the global optimization of force
field parameters using experimental data. It is hoped that the present
effort will further the application of the Drude polarizable force
field in molecular simulations including drug design and discovery.