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.

The tryptophyl-glycine (Trp-Gly) and tryptophyl-glycyl-glycine (Trp-Gly-Gly) peptides have been studied by means of molecular dynamic simulations combined with high-level correlated ab initio quantum chemical and statistical thermodynamic calculations. The lowest energy conformers were localized in the free energy surface. The structures of the different Trp-Gly and Trp-Gly-Gly conformers coexisting in the gas phase have been for the first time reported and their scaled theoretical IR spectra unambiguously assigned and compared with previous gas-phase experimental results. Common geometrical features have been systematically observed for the sequence Trp, Trp-Gly, and Trp-Gly-Gly. In addition, the peptide backbone of Trp-Gly-Gly has been compared with that of the previously studied Phe-Gly-Gly (Reha, D. et. al. Chem. Eur. J. 2005, 11, 6803). From the observed systematic structural behavior between these peptide analogues, it is expected that the gas-phase conformers of other similar aromatic small peptides would present equivalent geometries. The DFT methodology failed to describe the potential energy surface of the studied peptides since the London dispersion energy (not covered in DFT) plays a significant role in the stabilization of most stable conformers.

The free-energy surface (FES) of glycyl-phenylalanyl-alanine (GFA) tripeptide was explored by molecular dynamics (MD) simulations in combination with high-level correlated ab initio quantum chemical calculations and metadynamics. Both the MD and metadynamics employed the tight-binding DFT-D method instead of the AMBER force field, which yielded inaccurate results. We classified the minima localised in the FESs as follows: a) the backbone-conformational arrangement; and b) the existence of a COOH...OC intramolecular H-bond (families CO(2)H(free) and CO(2)H(bonded)). Comparison with experimental results showed that the most stable minima in the FES correspond to the experimentally observed structures. Remarkably, however, we did not observe experimentally the CO(2)H(bonded) family (also predicted by metadynamics), although its stability is comparable to that of the CO(2)H(free) structures. This fact was explained by the former's short excited-state lifetime. We also carried out ab initio calculations using DFT-D and the M06-2X functional. The importance of the dispersion energy in stabilising peptide conformers is well reflected by our pioneer analysis using the DFT-SAPT method to explore the nature of the backbone/side-chain interactions.

Correlated ab initio calculations on large systems, such as the popular MP2 (or RI-MP2) method, suffer from the intramolecular basis set superposition error (BSSE). This error is typically manifested in molecules with folded structures, characterized by intramolecular dispersion interactions. It can dramatically affect the energy differences between various conformers as well as intramolecular stabilities, and it can even impair the accuracy of the predictions of the equilibrium molecular structures. In this study, we will present two extreme cases of intramolecular BSSE, the internal stability of [n]helicene molecules and the relative energies of various conformers of phenylalanyl-glycyl-phenylalanine tripeptide (Phe-Gly-Phe), and compare the calculated data with benchmark values (experimental or high-level theoretical data). As a practical and cheap solution to the accurate treatment of the systems with large anticipated value of intramolecular BSSE, the recently developed density functional method augmented with an empirical dispersion term (DFT-D) is proposed and shown to provide very good results in both of the above described representative cases.

Cyanides and isocyanides of first-row transition metal M(CN) (M=Sc-Zn) are investigated with quantum chemistry techniques, providing predictions for their molecular properties. A careful analysis of the competition between cyanide and isocyanide isomers along the transition series has been carried out. In agreement with the experimental observations, late transition metals (Co-Zn) clearly prefer a cyanide arrangement. On the other hand, early transition metals (Sc-Fe), with the only exception of the Cr(CN) system, favor the isocyanide isomer. The theoretical calculations predict the following unknown isocyanides, ScNC(3Delta), TiNC(4Phi), VNC(5Delta), and MnNC(7Sigma+), and agree with the experimental observation of FeNC(6Delta) and the CrCN(6Sigma+) cyanide. First-row transition metal cyanides and isocyanides are predicted to have relatively large dissociation energies with values within the range 80-101 kcal mol(-1), except Zn(CN), which has a dissociation energy around 50-55 kcal mol(-1), and low isomerization barriers. A detailed analysis of the bonding has been carried out employing the topological analysis of the charge density and an energy decomposition analysis. The role of the covalent and electrostatic contributions to the metal-ligand bonding, as well as the importance of pi bonding, are discussed.

The coupled cluster method covering single and double electron excitations iteratively and triple electron excitations non-iteratively (CCSD(T)) provides highly accurate energies, geometries and various properties for molecular clusters and complex molecular systems. In our laboratory, we consistently use the CCSD(T) method extrapolated to complete basis set limit (CBS) and during the past several years we have collected data for several hundreds of molecular complexes and complex molecular systems (mostly peptides). These calculations are, however, time consuming and for systems with more than about 50 atoms are still impractical. This is due to the fact that the method scales as N 7 where N is the number of basis functions. To attain similar accuracy for extended systems requires the use of new techniques,