A sobering assessment of small-molecule force field methods for low energy conformer predictions

International Journal of Quantum Chemistry

4 years ago

A sobering assessment of small-molecule force field methods for low energy conformer predictions

John A. Keith, Ilana Y. Kanal, Geoffrey R. Hutchison

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. Almost all small molecules have multiple conformers, which are typically evaluated using classical molecular mechanics forcefields, such as MMFF94. Unfortunately, such methods exhibit poor correlation with PM7 and DFT energies and geometries. In general, conformer energies and rankings should be performed with PM7-optimized geometries and DFT single-points.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/qua.25512