Validation
Challenge of Density-Functional Theory
for PeptidesExample of Ac-Phe-Ala<sub>5</sub>‑LysH<sup>+</sup>
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Abstract
We assess the performance of a group
of exchange-correlation functionals
for predicting the secondary structure of peptide chains, up to a
new many-body dispersion corrected hybrid density functional, dubbed
PBE0+MBD* by its original authors. For the purpose of validation,
we first compare to published, high-level benchmark conformational
energy hierarchies (coupled cluster at the singles, doubles, and perturbative
triples level, CCSD(T)) for 73 conformers of small three-residue peptides,
establishing that the van der Waals corrected PBE0 functional yields
an average error of only ∼20 meV (∼0.5 kcal/mol). This
compares to ∼40–50 meV for nondispersion corrected PBE0
and 40–100 meV for different empirical force fields (estimated
for the alanine tetrapeptide). For longer peptide chains that form
a secondary structure, CCSD(T) level benchmark data are currently
unaffordable. We thus turn to the <i>experimentally</i> well
studied Ac-Phe-Ala<sub>5</sub>-LysH<sup>+</sup> peptide, for which
four closely competing conformers were established by infrared spectroscopy.
For comparison, an exhaustive theoretical conformational space exploration
yields at least 11 competing low energy minima. We show that (i) the
many-body dispersion correction, (ii) the hybrid functional nature
of PBE0+MBD*, and (iii) zero-point corrections are needed to reveal
the four experimentally observed structures as the minima that would
be populated at low temperature