Optimized Lennard-Jones Parameters for Druglike Small Molecules

Meaningful
efforts in computer-aided drug design (CADD) require
accurate molecular mechanical force fields to quantitatively characterize
protein–ligand interactions, ligand hydration free energies,
and other ligand physical properties. Atomic models of new compounds
are commonly generated by analogy from the predefined tabulated parameters
of a given force field. Two widely used approaches following this
strategy are the General Amber Force Field (GAFF) and the CHARMM General
Force Field (CGenFF). An important limitation of using pretabulated
parameter values is that they may be inadequate in the context of
a specific molecule. To resolve this issue, we previously introduced
the General Automated Atomic Model Parameterization (GAAMP) for automatically
generating the parameters of atomic models of small molecules, using
the results from ab initio quantum mechanical (QM) calculations as
target data. The GAAMP protocol uses QM data to optimize the bond,
valence angle, and dihedral angle internal parameters, and atomic
partial charges. However, since the treatment of van der Waals interactions
based on QM is challenging and may often be unreliable, the Lennard-Jones
6–12 parameters are kept unchanged from the initial atom types
assignments (GAFF or CGenFF), which limits the accuracy that can be
achieved by these models. To address this issue, a new set of Lennard-Jones
6–12 parameters was systematically optimized to reproduce experimental
neat liquid densities and enthalpies of vaporization for a large set
of 430 compounds, covering a wide range of chemical functionalities.
Calculations of the hydration free energy indicate that optimal accuracy
for these models is achieved when the molecule–water van der
Waals dispersion is rescaled by a factor of 1.115. The final optimized
model yields an average unsigned error of 0.79 kcal/mol in the hydration
free energies.