Toward Accurate Quantum Chemical Methods for Molecules of Increasing Dimension: The New Family of Pisa Composite Schemes.

The new versions of the Pisa composite scheme introduced in the present paper are based on the careful selection of different quantum chemical models for energies, geometries, and vibrational frequencies, with the aim of maximizing the accuracy of the overall description while retaining a reasonable cost for all the steps. In particular, the computation of accurate electronic energies has been further improved introducing more reliable complete basis set extrapolations and estimation of core-valence correlation, together with improved basis sets for third-row atoms. Furthermore, the reduced-cost frozen natural orbital (FNO) model has been introduced and validated for large molecules. Accurate molecular structures can be obtained avoiding complete basis set extrapolation and evaluating core-valence correlation at the MP2 level. Unfortunately, analytical gradients are not available for the FNO version of the model. Therefore, for large molecules, an accurate reduced-cost alternative is offered by evaluation of valence contributions with a double-hybrid functional in conjunction with the same MP2 contribution for core-valence correlation or by means of a one-parameter approximation. The same double-hybrid functional and basis set are employed to evaluate zero-point energies and partition functions. After the validation of the new models for small systems, a panel of molecular bricks of life has been used to analyze their performances for problems of current fundamental or technological interest. The fully black-box implementation of the computational workflow paves the way toward the accurate yet not prohibitively expensive study of medium- to large-sized molecules also by experimentally oriented researchers.

Accurate Structures and Rotational Constants of Steroid Hormones at DFT Cost: Androsterone, Testosterone, Estrone, ß-Estradiol, and Estriol.

A comprehensive analysis of the structural, conformational, and spectroscopic properties in the gas phase has been performed for five prototypical steroid hormones, namely, androsterone, testosterone, estrone, ß-estradiol, and estriol. The revDSD-PBEP86 double-hybrid functional in conjunction with the D3BJ empirical dispersion and a suitable triple-ζ basis set provides accurate conformational energies and equilibrium molecular structures, with the latter being further improved by proper account of core-valence correlation. Average deviations within 0.1% between computed and experimental ground state rotational constants are reached when adding to those equilibrium values vibrational corrections obtained at the cost of standard harmonic frequencies thanks to the use of a new computational tool. Together with the intrinsic interest of the studied hormones, the accuracy of the results obtained at DFT cost for molecules containing about 50 atoms paves the way toward the accurate investigations of other flexible bricks of life.

Toward an Accurate Black-Box Tool for the Kinetics of Gas-Phase Reactions Involving Barrier-less Elementary Steps.

An enhanced computational protocol has been devised for the accurate characterization of gas-phase barrier-less reactions in the framework of the reaction-path (RP) and variable reaction coordinate variational transition-state theory. In particular, the synergistic combination of density functional theory and Monte Carlo sampling to optimize reactive fluxes led to a reliable yet effective computational workflow. A black-box strategy has been developed for selecting the most suited density functional with reference to a high-level one-dimensional reference potential. At the same time, different descriptions of hindered rotations are automatically selected, depending on the corresponding harmonic frequencies along the RP. The performance of the new tool is investigated by means of two prototypical reactions involving different degrees of static and dynamic correlation, namely, H2S + Cl and CH3 + CH3. The remarkable agreement of the computed kinetic parameters with the available experimental data confirms the accuracy and robustness of the proposed approach. Together with their intrinsic interest, these results also pave the way toward systematic investigations of gas-phase reactions involving barrier-less elementary steps by a reliable, user-friendly tool, which can be confidently used also by nonspecialists.

Accurate Thermochemical and Kinetic Parameters at Affordable Cost by Means of the Pisa Composite Scheme (PCS).

A new strategy for the computation at an affordable cost of geometrical structures, thermochemical parameters, and rate constants for medium-sized molecules in the gas phase is proposed. The most distinctive features of the new model are the systematic use of cc-pVnZ-F12 basis sets, the addition of MP2 core-valence correlation in geometry optimizations by a double-hybrid functional, the separate extrapolation of MP2 and post-MP2 contributions, and the inclusion of anharmonic contributions in zero-point energies and thermodynamic functions. A thorough benchmark based on a wide range of prototypical systems shows that the new scheme outperforms the most well-known model chemistries without the need for any empirical parameter. Additional tests show that the computed zero-point energies and thermal contributions can be confidently used for obtaining accurate thermochemical and kinetic parameters. Since the whole computational workflow is translated in a black-box procedure, which can be followed with standard electronic structure codes, the way is paved for the accurate yet not prohibitively expensive study of medium- to large-sized molecules also by nonspecialists.

DFT Meets Wave-Function Methods for Accurate Structures and Rotational Constants of Histidine, Tryptophan, and Proline.

A new computational strategy has been applied to the conformational and spectroscopic properties in the gas phase of amino acids with very distinctive features, ranging from different tautomeric forms (histidine) to ring puckering (proline), and heteroaromatic structures with non-equivalent rings (tryptophan). The integration of modern double-hybrid functionals and wave-function composite methods has allowed us to obtain accurate results for a large panel of conformers with reasonable computer times. The remarkable agreement between computations and microwave experiments allows an unbiased interpretation of the latter in terms of stereoelectronic effects.

Accurate Structures and Spectroscopic Parameters of Guanine Tautomers in the Gas Phase by the Pisa Conventional and Explicitly Correlated Composite Schemes (PCS and PCS-F12).

A general strategy for the accurate computation of structural and spectroscopic properties of biomolecule building blocks in the gas phase is proposed and validated for tautomeric equilibria. The main features of the new model are the inclusion of core-valence correlation in geometry optimizations by a double hybrid functional and the systematic use of wave-function composite methods in conjunction with cc-pVnZ-F12 basis sets with separate extrapolation of MP2 and post-MP2 contributions. The resulting Pisa composite scheme employing conventional (PCS) or explicitly correlated (PCS-F12) approaches is applied to the challenging problem of guanine tautomers in the gas phase. The results are in remarkable agreement with the experimental structures, relative stabilities, and spectroscopic signatures of different tautomers. The accuracy of the results obtained at reasonable cost by means of black-box parameter-free approaches paves the way toward systematic investigations of other molecular bricks of life also by non-specialists.

Toward Accurate yet Effective Computations of Rotational Spectroscopy Parameters for Biomolecule Building Blocks.

The interplay of high-resolution rotational spectroscopy and quantum-chemical computations plays an invaluable role in the investigation of biomolecule building blocks in the gas phase. However, quantum-chemical methods suffer from unfavorable scaling with the dimension of the system under consideration. While a complete characterization of flexible systems requires an elaborate multi-step strategy, in this work, we demonstrate that the accuracy obtained by quantum-chemical composite approaches in the prediction of rotational spectroscopy parameters can be approached by a model based on density functional theory. Glycine and serine are employed to demonstrate that, despite its limited cost, such a model is able to predict rotational constants with an accuracy of 0.3% or better, thus paving the way toward the accurate characterization of larger flexible building blocks of biomolecules.

Absorption Spectra of Flexible Fluorescent Probes by a Combined Computational Approach: Molecular Dynamics Simulations and Time-Dependent Density Functional Theory.

A detailed understanding and interpretation of absorption spectra of molecular systems, especially in condensed phases, requires computational models that allow their structural and electronic features to be connected to the observed macroscopic spectra. This work is focused on modeling the electronic absorption spectrum of a fluorescent probe, namely, the 9-(4-((bis(2-((2-(ethylthio)ethyl)thio)ethyl)amino)methyl)phenyl)-6-(pyrrolidin-1-yl)-3H-xanthen-3-one molecule, depicted by a combined classical-quantum chemical approach. Particularly, first classical molecular dynamics (MD) has been used to explore the configurational space, and next, the absorption spectrum has been reconstructed by averaging the results of time-dependent density functional theory (TD-DFT) calculations performed on equispaced molecular conformations extracted from MD to properly sample the configurational space explored at finite temperature. To verify the effect of molecular conformation on the spectral profile, the generated electronic absorption spectra were compared with those obtained considering a single structure corresponding to the optimized one, an approach also referred to as static. This comparison allows one to highlight a sizable though small shift between the maxima of the corresponding reconstructed absorption spectra, highlighting the importance of conformational sampling in the case of this rather flexible molecule. Four different exchange and correlation functionals (PBE, BLYP, PBE0, B3LYP) were considered to compute vertical transition via TD-DFT calculations. From the results obtained in gas and in condensed, here solution, phases, it appears that the magnitude of the shift is actually more affected by the phase in which the system is found than by the functional used. This fact underlines the central importance of conformational mobility, that is flexibility, of this molecule. From a more quantitative point of view, a comparison with available experimental data shows that hybrid functionals, such as PBE0 and B3LYP, enable one to faithfully reproduce the observed absorption maxima.