Structure and IR Spectrum of Phenylalanyl–Glycyl–Glycine Tripetide in the Gas‐Phase: IR/UV Experiments, Ab Initio Quantum Chemical Calculations, and Molecular Dynamic Simulations

Abstract

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.

Accurate quantum chemical energies for tetrapeptide conformations: why MP2 data with an insufficient basis set should be handled with caution

“…However, due to their computational cost, their applicability has been restricted to smaller systems such as amino acids, and di-and tripeptides. 5,6 Tetrapeptides are the smallest model systems that are able to mimic the typical hydrogen-bond pattern in a-helices. They are therefore of particular biological interest, and QM treatments of them have been reported since the late 1990s.…”

Quantum Chemical Benchmark Energy and Geometry Database for Molecular Clusters and Complex Molecular Systems (www.begdb.com): A Users Manual and Examples

“…We have also covered the phenomena of halogen bonding 3 . Aside from noncovalent complexes, we have studied conformers of small peptides [4][5][6] at the same level of theory. This list is not final; we are working on more systematic high-level studies.…”

Structure of isolated tyrosyl-glycyl-glycine tripeptide. A comparative conformational study with peptides containing an aromatic ring

“…Also, B3LYP/6-31+G(d) and MP2/6-31+G(d) calculations predicted markedly different structures for the tyrosilglycine (YG) dipeptide [21]. The same conformational behaviour discrepancy between these two methods was observed for a number of other molecules containing an aromatic ring in addition to a flexible side chain, WG [17][18][19] and WGG [18,19]. Further investigation suggested that the very different structures obtained by B3LYP and MP2 are likely caused by dispersion (a true physical effect, underestimated by B3LYP) as well as large basis set superposition errors (BSSE, an artificial attraction) in the MP2 calculations [22].…”

“…One of the most important reasons for this inaccuracy might be the fact that they work with effective average charges (over all existing structures), which may be far from the charges that properly describe each individual structure. It has recently been proven that the scan of the PES of FGG [17] and GFA [46] by using the AMBER empirical force field fails mainly due to a large variety of atomic charges for individual conformers. These calculations have demonstrated that introducing an average charge brings some uncertainty that results in incorrect structural predictions when an empirical potential is used.…”

“…There are four aromatic amino acids found in proteins, namely, phenylalanine (F), tyrosine (Y), tryptophan (W), and histidine (H). The structure of these amino acids and of some aromatic small peptides such as phenylalanylglycyl-glycine (FGG), tryptophyl-glycine (WG) and tryptophyl-glycyl-glycine (WGG), have already been reported by means of molecular dynamic simulations combined with high-level correlated ab initio quantum chemical calculations [17][18][19]. The structure of the tyrosyl-glycyl-glycine (YGG) peptide has recently been investigated using a combination of different strategies that employ a hierarchy of electronic structure theory [20].…”