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