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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 experimentally well studied Ac-Phe-Ala5-LysH(+) 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.

We study the initial steps of the interaction of water molecules with two unsolvated peptides: Ac-Ala(5)-LysH(+) and Ac-Ala(8)-LysH(+). Each peptide has two primary candidate sites for water adsorption near the C-terminus: a protonated carboxyl group and the protonated ammonium group of LysH(+), which is fully hydrogen-bonded (self-solvated) in the absence of water. Earlier experimental studies have shown that H(2)O adsorbs readily at Ac-Ala(5)-LysH(+) (a non-helical peptide) but with a much lower propensity at Ac-Ala(8)-LysH(+) (a helix) under the same conditions. The helical conformation of Ac-Ala(8)-LysH(+) has been suggested as the origin of the different behavior. We here use first-principles conformational searches (all-electron density functional theory based on a van der Waals corrected version of the PBE functional, PBE+vdW) to study the microsolvation of Ac-Ala(5)-LysH(+) with one to five water molecules and the monohydration of Ac-Ala(8)-LysH(+). In both cases, the most favorable water adsorption sites break intramolecular hydrogen bonds associated with the ammonium group, in contrast to earlier suggestions in the literature. A simple thermodynamic model yields Gibbs free energies ΔG(0)(T) and equilibrium constants in agreement with experiments. A qualitative change of the first adsorption site does not occur. For few water molecules, we do not consider carboxyl deprotonation or finite-temperature dynamics, but in a liquid solvent, both effects would be important. Exploratory ab initio molecular dynamics simulations illustrate the short-time effects of a droplet of 152 water molecules on the initial unsolvated conformation, including the deprotonation of the carboxyl group. The self-solvation of the ammonium group by intramolecular hydrogen bonds is lifted in favor of a solvation by water.