Benchmarking Force Field and the ANI Neural Network Potentials for the Torsional Potential Energy Surface of Biaryl Drug Fragments

Lahey, Shae-Lynn; Phuc, Tu Nguyen Thien; Rowley, Christopher N.

doi:10.26434/chemrxiv.12780056.v1

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“…Small chemical changes to molecules, both local and remote, can drastically alter their electronic properties. This poses a challenge to force field parametrization, specifically that of torsion parameters which rely on computationally expensive QC torsion scans for reference data [41]. Given how poorly QC torsion scans scale with molecular size, molecules are fragmented to smaller entities to generate the reference data.…”

Section: Resultsmentioning

confidence: 99%

“…However, since atom types are locally defined, they do not always capture long-range effects such as conjugation. This is especially problematic for torsions since the torsion energy function (or profile) of a bond is determined by a combination of local and non-local effects such as conjugation, hyperconjugation, sterics, and electrostatics [37,38,39,40,41]. In this study, we define local atoms as those within two bonds of the central bond of a torsion, and remote atoms as any atom beyond those two bonds.…”

Section: Theory and Definitionsmentioning

confidence: 99%

See 1 more Smart Citation

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

Stern

Bayly²,

Smith

et al. 2020

Preprint

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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.

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Section: Resultsmentioning

confidence: 99%