A Sobering Assessment of Small-Molecule Force Field Methods for Low Energy Conformer Predictions

TL;DR

This study evaluates the effectiveness of common small-molecule force fields in predicting low-energy conformers, revealing their poor correlation with higher-level methods and suggesting improvements for conformer screening.

Contribution

The paper provides a large-scale assessment of force field accuracy for conformer prediction and offers recommendations to improve computational screening methods.

Findings

Classical force fields show poor correlation with DFT and semiempirical energies.

Semiempirical PM7 correlates better with DFT than classical force fields.

Recommendations are made for more reliable conformer screening.

Abstract

We have carried out a large scale computational investigation to assess the utility of common small-molecule force fields for computational screening of low energy conformers of typical organic molecules. Using statistical analyses on the energies and relative rankings of up to 250 diverse conformers of 700 different molecular structures, we find that energies from widely-used classical force fields (MMFF94, UFF, and GAFF) show unconditionally poor energy and rank correlation with semiempirical (PM7) and Kohn-Sham density functional theory (DFT) energies calculated at PM7 and DFT optimized geometries. In contrast, semiempirical PM7 calculations show significantly better correlation with DFT calculations and generally better geometries. With these results, we make recommendations to more reliably carry out conformer screening.