Capturing non-local through-bond effects in molecular mechanics force fields I: Fragmenting molecules for quantum chemical torsion scans [Article v1.1]

Abstract

Accurate molecular mechanics force fields for small molecules are essential for predicting protein-ligand binding affinities in drug discovery and understanding the biophysics of biomolecular systems. Torsion potentials derived from quantum chemical (QC) calculations are critical for determining the conformational distributions of small molecules, but are computationally expensive and scale poorly with molecular size. To reduce computational cost and avoid the complications of distal through-space intramolecular interactions, molecules are generally fragmented into smaller entities to carry out QC torsion scans. However, torsion potentials, particularly for conjugated bonds, can be strongly affected by through-bond chemistry distal to the torsion itself. Poor fragmentation schemes have the potential to significantly disrupt electronic properties in the region around the torsion by removing important, distal chemistries, leading to poor representation of the parent molecule’s chemical environment and the resulting torsion energy profile. Here we show that a rapidly computable quantity, the fractional Wiberg bond order (WBO), is a sensitive reporter on whether the chemical environment around a torsion has been disrupted. We show that the WBO can be used as a surrogate to assess the robustness of fragmentation schemes and identify conjugated bond sets. We use this concept to construct a validation set by exhaustively fragmenting a set of druglike organic molecules and examine their corresponding WBO distributions derived from accessible conformations that can be used to evaluate fragmentation schemes. To illustrate the utility of the WBO in assessing fragmentation schemes that preserve the chemical environment, we propose a new fragmentation scheme that uses rapidly-computable AM1 WBOs, which are available essentially for free as part of standard AM1-BCC partial charge assignment. This approach can simultaneously maximize the chemical equivalency of the fragment and the substructure in the larger molecule while minimizing fragment size to accelerate QC torsion potential computation for small molecules and reducing undesired through-space steric interactions.

Benchmark assessment of molecular geometries and energies from small molecule force fields

“…One key challenge going forward will be to continue improving treatment of problematic areas of chemical space and expanding coverage. In parallel, future OpenFF updates will include improved treatment of torsions (via Wiberg bond order-based parameter interpolation 97 which was recently implemented in our toolkit) and better handling of trivalent nitrogen geometries 98 which we hope will boost performance further.…”

Benchmark Assessment of Molecular Geometries and Energies from Small Molecule Force Fields

“…In parallel, future OpenFF updates will include improved treatment of torsions (via Wiberg bond order-based parameter interpolation 94 which was recently implemented in our toolkit)…”

Capturing non-local through-bond effects in molecular mechanics force fields: II. Using fractional bond orders to fit torsion parameters

“…Given how critical torsion parameters are in determining conformation distributions in simulations, it is prudent for them to be accurately parameterized. Third, torsional potentials can be strongly influenced by distal substituents due to changes in conjugation or hypercojugation, a nonlocal effect very difficult to represent in a force field that uses only the local chemical environment to define parameters [67].…”

“…The pink distribution was calculated over 366 distributions of 366 bonds in different chemical environments of 140,602 fragments. These fragments were taken from the validations set of fragmenter, an automated approach that uses WBOs to fragment molecules for QC torsion scans with minimal perturbation to the QC torsion profile [67].…”