Computational chiroptical spectroscopy of bioactive molecules: the influence of conformational flexibility and solvation

none3noThe close relationship between chirality and the differential interaction with polarised radiation is the physical foundation upon which chiroptical techniques, such as optical rotatory dispersion (ORD) and circular dichroism (CD), have established themselves among the main tools for the stereochemical characterisation of chemical systems. The interpretation of chiroptical properties, however, requires accurate theoretical models in order to unveil the correlation between the dissymmetric disposition of atoms at the molecular level and the macroscopic onset of optical activity. In the last decades, the impressive improvement in the accuracy of quantum chemical models and the availability of increasingly powerful computational resources have laid the path to a renewed interest in the stereochemical characterisation of large systems by theoretical determination of their chiroptical properties. [1] Time-dependent density functional theory (TD-DFT) has become the standard method for chiroptical properties calculations on small-to-medium sized molecules, due to the reasonable balance between chemical accuracy and computational efficiency. The application to larger systems seems to have a very promising perspective; however, the large number of conformations at equilibrium for large and flexible molecules, the shortcomings in the proper description of weak interactions like dispersion forces, and the high demands in terms of computational resources are still limiting a broader applicability of TD-DFT methods to pharmaceutically relevant systems. [2] Among the factors influencing the conformational flexibility of a system, solvation effects represent a very challenging task in computational chemistry. Solvation effects are usually described by continuum solvation models, which are able to account for long-range perturbations due to the solvent bulk but fail in the description of local interactions, like hydrogen bonds. This shortcoming is usually overcome by the introduction of a small number of solvent molecules around the chromophores in order to form a solvation cluster. Solvation effects, however, are dynamic phenomena, and the accurate selection of the number and position of solvent molecules in the cluster is a critical factor for the accuracy of the calculation. Moreover, rare phenomena, such as the chiral imprint of a chiral solute inducing optical activity on the solvation shells of non-chiral solvents, are still open fields of research. [3] The feasibility and reliability of a computational protocol for the stereochemical characterisation of large and flexible bioactive molecules and for an accurate description of solvation effects on chiroptical properties will be discussed on the basis of some ongoing case studies. [4] The resolution of identity (RI) approximation combined with B97D, which includes empirical dispersion corrections, allows a good balance between computational efficiency and chemical accuracy; on the other hand, PBE0 is able to reproduce the intense experimental ECD bands usually found in the high-energy spectral region. This computational protocol is able to provide fairly accurate and reliable predictions of the chiroptical properties of large and conformationally flexible systems, and might be successfully applied for the stereochemical characterization of similar systems. [1] P. Polavarapu, Chem. Rec., 2007, 7, 125–136. [2] L. Goerigk et al., in Comprehensive chiroptical spectroscopy 1, 2011, Wiley: New York, pp. 643–673. [3] B. Mennucci et al., Chirality, 2011, 23, 717–729. [4] ISCRA project IsC08_SCCFPM (ID: HP10CU0YHL) granted by CINECA, Bologna, Italy.openDaniele Tedesco; Riccardo Zanasi; Carlo BertucciDaniele Tedesco; Riccardo Zanasi; Carlo Bertucc