By considering a large number of diverse organic molecules with many poses per molecule, we seek to sample a wide variety of conformer energy preferences (e.g., intramolecular hydrogen and halogen bonding, electrostatic interactions, etc.). While using optimized low-energy conformers may under-estimate the degree of correlation for high-energy structures,\cite{Sharapa_2018} we believe the current work is a challenging but useful comparison. In general, such high-energy geometries reflect steric repulsion more than the diverse types of interactions driving low-energy geometries.
Moreover, many computational predictions rely on Boltzmann-weighted averages of multiple thermally accessible conformers, including NMR prediction,\cite{Lodewyk_2011,Grimme_2004} reactions, and even understanding the effects of dipole moments on solvent viscosity.\cite{Vo_2019}
Comparison of single points vs. DLPNO-CCSD(T)
For comparison, we considered a wide variety of currently available computational methods:
- Common classical organic force fields: MMFF94,\cite{Halgren_1996,Halgren:1996kn,Halgren:1996ew,Halgren:1996hj,Halgren:1996ux} UFF,\cite{Rappe_1992} GAFF\cite{Wang_2004}
- Semiempirical wave function: PM7\cite{Stewart_2012}
- Density functional tight binding: GFN0,\cite{Pracht_2019} GFN1,\cite{Grimme_2017} GFN2\cite{Bannwarth_2018}
- Low-cost density functional approximations: PBEh-3c,\cite{Grimme_2015} B97-3c\cite{Brandenburg_2018}
- Dispersion-corrected density functionals: B3LYP,\cite{Lee_1988,Becke_1988,Stephens_1994,Vosko_1980} PBE\cite{Perdew_1997,Perdew_1996}, ωB97X-D\cite{Chai_2008} with dispersion correction (using def2-TZVP basis set\cite{Weigend_2005,Weigend_2006})
- Møller-Plesset RI-MP2\cite{Kossmann_2010} (cc-pVTZ basis set\cite{Dunning_1989,Kendall_1992})
In the case of B3LYP and PBE dispersion-corrected functionals, we also considered both the commonly-used double-zeta def2-SVP and triple-zeta def2-TZVP basis sets to understand the effects of basis set size. For B3LYP, PBE, and ωB97X, we also considered the accuracy with and without dispersion correction.