A detailed quantum chemical study on five peptides (WG, WGG, FGG, GGF and GFA) containing the residues phenylalanyl (F), glycyl (G), tryptophyl (W) and alanyl (A) -- where F and W are of aromatic character -- is presented. When investigating isolated small peptides, the dispersion interaction is the dominant attractive force in the peptide backbone-aromatic side chain intramolecular interaction. Consequently, an accurate theoretical study of these systems requires the use of a methodology covering properly the London dispersion forces. For this reason we have assessed the performance of the MP2, SCS-MP2, MP3, TPSS-D, PBE-D, M06-2X, BH&H, TPSS, B3LYP, tight-binding DFT-D methods and ff99 empirical force field compared to CCSD(T)/complete basis set (CBS) limit benchmark data. All the DFT techniques with a '-D' symbol have been augmented by empirical dispersion energy while the M06-2X functional was parameterized to cover the London dispersion energy. For the systems here studied we have concluded that the use of the ff99 force field is not recommended mainly due to problems concerning the assignment of reliable atomic charges. Tight-binding DFT-D is efficient as a screening tool providing reliable geometries. Among the DFT functionals, the M06-2X and TPSS-D show the best performance what is explained by the fact that both procedures cover the dispersion energy. The B3LYP and TPSS functionals-not covering this energy-fail systematically. Both, electronic energies and geometries obtained by means of the wave-function theory methods compare satisfactorily with the CCSD(T)/CBS benchmark data.

We investigated the potential-energy surface (PES) of the phenylalanyl-glycyl-glycine tripeptide in the gas phase by means of IR/UV double-resonance spectroscopy, and quantum chemical and statistical thermodynamic calculations. Experimentally, we observed four conformational structures and we recorded their IR spectra in the spectral region of 3000-4000 cm(-1). Computationally, we investigated the PES by a combination of molecular dynamics/quenching procedures with high-level correlated ab initio calculations. We found that neither empirical potentials nor various DFT functionals provide satisfactory results. On the other hand, the approximative DFT method covering the dispersion energy yields a reliable set of the most stable structures, which we subsequently investigated with an accurate, correlated ab initio treatment. The global minimum contains three moderately strong intramolecular hydrogen bonds and is mainly stabilized by London dispersion forces between the phenyl ring, the carboxylic acid group, and various peptide bonds. A proper description of the last type of interaction requires accurate correlated ab initio calculations, including the complete basis set limit of the MP2 method and CCSD(T) correction terms. Since in our beam experiments the conformations are frozen by cooling from a higher temperature, it is necessary to localize the most stable structures on the free-energy surface rather than on the PES. We used two different procedures (rigid rotor/harmonic oscillator/ideal gas approximation based on ab initio characteristics and evaluation of relative populations from the molecular dynamic simulations using the AMBER potential) and both yield four structures, the global minimum and three local minima. These four structures were among the 15 most energetically stable structures obtained from accurate ab initio optimization. The calculated IR spectra for these four structures agree well with the experimental frequencies, which validates the localization procedure.

Among the forces responsible for shaping proteins, interactions between side chains of aromatic residues play an important role as they are involved in the secondary and the tertiary structures of proteins contributing to the formation of hydrophobic domains. The purpose of this paper is to document this interaction in two capped dipeptides modeling a segment of a protein chain having two consecutive Phe residues, Ac-Phe-Phe-NH(2) and Ac-Phe-D-Phe-NH(2). These two molecules have been investigated in the gas phase by IR/UV double resonance spectroscopy, and the assignment of the observed conformers has been done by comparison with quantum chemistry calculations. Both peptides are found to adopt a beta-turn type I conformation stabilized by an edge-to-face interaction between the two aromatic rings. Comparison with other dipeptides in the literature demonstrates the impact of this aromatic-aromatic interaction on the shape adopted by the peptide chain, and its role among the other shaping forces (H-bonds, NH-pi interactions) is discussed. As an illustration, the H-bond strength is found to be significantly lower in the beta-turn type I conformer, in which the two rings interact, as compared to the similar conformer where such an interaction does not exist. This structural feature due to the backbone distortion induced by the interaction between the aromatic rings makes this system a good test for evaluating the ability of computational methods to correctly account for the competition between these forces. MP2, SCS-MP2, DFT, and DFT-D methods have been assessed in this respect. Comparison between geometries, energies, and frequency calculations illustrate their respective limitations in describing conformations resulting from a subtle equilibrium between the several interactions at play.