Development and Benchmarking of Open Force Field v1.0.0—the Parsley Small-Molecule Force Field

Abstract

We present a methodology for defining and optimizing a general force field for classical molecular simulations, and we describe its use to derive the Open Force Field 1.0.0 smallmolecule force field, codenamed Parsley. Rather than using traditional atom typing, our approach is built on the SMIRKSnative Open Force Field (SMIRNOFF) parameter assignment formalism, which handles increases in the diversity and specificity of the force field definition without needlessly increasing the complexity of the specification. Parameters are optimized with the ForceBalance tool, based on reference quantum chemical data that include torsion potential energy profiles, optimized gas-phase structures, and vibrational frequencies. These quantum reference data are computed and are maintained with QCArchive, an opensource and freely available distributed computing and database software ecosystem. In this initial application of the method, we present essentially a full optimization of all valence parameters and report tests of the resulting force field against compounds and data types outside the training set. These tests show improvements in optimized geometries and conformational energetics and demonstrate that Parsley's accuracy for liquid properties is similar to that of other general force fields, as is accuracy on binding free energies. We find that this initial Parsley force field affords accuracy similar to that of other general force fields when used to calculate relative binding free energies spanning 199 protein−ligand systems. Additionally, the resulting infrastructure allows us to rapidly optimize an entirely new force field with minimal human intervention.

Pre-Exascale Computing of Protein–Ligand Binding Free Energies with Open Source Software for Drug Design

“…MATCH 20 was used for assigning the CGENFF v3.0.1 parameters. We have also included a version v1.2.0 Parsley of the recently developed OpenFF 21 force field. The OpenFF topologies were generated using the OpenFF toolkit 22 and converted to GROMACS topologies using ParmEd.…”

Computational Modeling of Supramolecular Metallo-organic Cages–Challenges and Opportunities

“…72 Several force fields exist for describing organic molecules, including the universal force field (UFF), 73 the general AMBER force field (GAFF), 74 the CHARMM general force field (CGenFF), 75 the optimized potentials for liquid simulation force field (OPLS), 76 and the OpenFF family. 77 The UFF includes parameters for most atoms of the periodic table (including metals) and has also been extended to metal–organic frameworks (MOFs, UFF4MOF). 78 These FFs have been carefully parametrized to reproduce, for example, hydration free energies, partition coefficients, QM energy profiles, or vibrational frequencies, often targeting biological systems; however, their intrinsic simplicity means that they provide limited quantitative estimates of, for example, binding free energies.…”

Mechanistic Insights into Passive Membrane Permeability of Drug-Like Molecules from a Weighted Ensemble of Trajectories

“…The final system used in the WE simulations was prepared using several individually constructed molecular systems that were pieced together in the following way. First, ParmEd 44 was used to generate input files containing Open Force Field Parsley v1.3.1a1 force field 45 parameters for the drug-like molecule, as well as Amber LIPID17 46,47 parameters for the POPC membrane. Next, an initial solvated POPC membrane configuration was generated using the CHARMM-GUI v2.0 with the Membrane Builder input generator module, and 50 POPC molecules per leaflet in a solution of TIP3P water molecules.…”