The Melatonin Conformer Space: Benchmark and Assessment of Wave Function and DFT Methods for a Paradigmatic Biological and Pharmacological Molecule

Reference quality
conformational energies have been obtained for
the 52 unique conformers of melatonin by means of explicitly correlated
ab initio methods as well as the ccCA composite method. These data
have then been used to evaluate more approximate methods, including
a variety of density functionals both on their own and paired with
various empirical dispersion corrections. Owing to the presence of
internal contacts of the C–H···O and C–H···N
variety, basis set convergence is much slower than for alkane conformers,
for example, and basis sets of aug-cc-pVQZ or def2-QZVP quality seem
to be required to obtain firm estimates of the basis set limit. Not
just HF, but also many DFT functionals, will transpose the two lowest
conformers unless empirical dispersion corrections are added. Somewhat
surprisingly, many DFT functionals reproduce the reference data to
fairly high accuracy when combined with the D3BJ empirical dispersion
correction or the “nonlocal” Vydrov–Van Voorhis
dispersion model. The two best performers including dispersion corrections
are the double hybrids DSD-PBEP86-D3BJ and B2GP-PLYP-D; if no such
correction is permitted, then M06-2X puts in the best performance.
Of lower-cost ab initio-like models, MP2.5 yields the best performance,
followed by SCS-MP2.