Quantification of thermal ring flexibilities of aromatic and heteroaromatic compounds

The consequences of thermal fluctuations occurring at room temperatures on the aromatic character of a broad group of compounds were analyzed in three distinct ways. First of all, the ring deformations were modeled along normal coordinates coming from quantum thermo-chemistry computations. The amplitudes of vibrations were estimated according to absorbed energies at room temperature. Alternatively, in-plane and out-of-plane ring deformations were modeled via scanning procedure with partial relaxation of the molecular geometry. The influence of ring deformations on π–electron delocalization was expressed in terms of HOMA values. Besides, the ring deformability was defined as the averaged change of bond angles or dihedral angles constituting the ring that was associated with 1.5 kcal mol-1 increase of the system energy. The molecules structures adopted during vibrations at room temperature can lead to significant heterogeneity of structural index of aromaticity. The broad span of HOMA values was obtained for analyzed five- or six-membered aromatic and heteroaromatic rings. However, the averaged values obtained for such fluctuations almost perfectly match HOMA values of molecule in the ground state. It has been demonstrated that the ring deformability imposed by bond angle changes is much smaller than for dihedral angles with the same rise of system energy. Interestingly in the case of out-of-plane vibrations modeled by scanning procedure there is observed linear correlation between ring deformability and HOMA values. Proposed method for inclusion of thermal vibrations in the framework of π–electron delocalization provides natural shift of the way of thinking about aromaticity from a static quantity to a dynamic and heterogeneous one due to inclusion of a more realistic object of analysis – thermally deformed structures. From this perspective the thermal fluctuations are supposed to be non-negligible contributions to aromaticity phenomenon

Peptide Bond Distortions from Planarity: New Insights from Quantum Mechanical Calculations and Peptide/Protein Crystal Structures

By combining quantum-mechanical analysis and statistical survey of peptide/protein structure databases we here report a thorough investigation of the conformational dependence of the geometry of peptide bond, the basic element of protein structures. Different peptide model systems have been studied by an integrated quantum mechanical approach, employing DFT, MP2 and CCSD(T) calculations, both in aqueous solution and in the gas phase. Also in absence of inter-residue interactions, small distortions from the planarity are more a rule than an exception, and they are mainly determined by the backbone ψ dihedral angle. These indications are fully corroborated by a statistical survey of accurate protein/peptide structures. Orbital analysis shows that orbital interactions between the σ system of Cα substituents and the π system of the amide bond are crucial for the modulation of peptide bond distortions. Our study thus indicates that, although long-range inter-molecular interactions can obviously affect the peptide planarity, their influence is statistically averaged. Therefore, the variability of peptide bond geometry in proteins is remarkably reproduced by extremely simplified systems since local factors are the main driving force of these observed trends. The implications of the present findings for protein structure determination, validation and prediction are also discussed