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.

Accurate Geometries of Large Molecules by Integration of the Pisa Composite Scheme and the Templating Synthon Approach.

An effective yet reliable computational workflow is proposed, which permits the computation of accurate geometrical structures for large flexible molecules at an affordable cost thanks to the integration of machine learning tools and DFT models together with reduced scaling computations of vibrational averaging effects. After validation of the different components of the overall strategy, a panel of molecules of biological interest have been analyzed. The results confirm that very accurate geometrical parameters can be obtained at reasonable cost for molecules including up to about 50 atoms, which are the largest ones for which comparison with high-resolution rotational spectra is possible. Since the whole computational workflow can be followed employing standard electronic structure codes, accurate results for large-sized molecules can be obtained at DFT cost also by nonspecialists.

Hunting for Complex Organic Molecules in the Interstellar Medium: The Role of Accurate Low-Cost Theoretical Geometries and Rotational Constants.

A new approach to computation at affordable cost of accurate geometrical structures and rotational constants for medium-sized molecules in the gas phase is further improved and applied to a large panel of interstellar complex organic molecules. The most distinctive feature of the new model is the effective inclusion of core-valence correlation and vibrational averaging effects in the framework of density functional theory (DFT). In particular, a double-hybrid functional in conjunction with a quadruple-ζ valence/triple-ζ polarization basis set is employed for geometry optimizations, whereas a cheaper hybrid functional in conjunction with a split-valence basis set is used for the evaluation of vibrational corrections. A thorough benchmark based on a wide range of prototypical systems shows that the new scheme approaches the accuracy of state-of-the-art wave function methods with the computational cost of the standard methods (DFT or MP2) routinely employed in the interpretation of microwave spectra. Since the whole computational workflow involves the postprocessing of the output of standard electronic structure codes by a new freely available web utility, 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 Spectroscopic Accuracy for the Structures of Large Molecules at DFT Cost: Refinement and Extension of the Nano-LEGO Approach.

The SE100 database collecting accurate equilibrium geometries of medium size molecules obtained by the semiexperimental (SE) approach has been extended to species containing Br and I atoms. This has allowed the determination of accurate linear regressions between DFT and SE values for all the main bonds and angles involving H, B, C, N, O, F, P, S, Cl, Br, and I atoms. An improved Nano-LEGO tool has been developed, which is based on suitable hybrid and double hybrid functionals and combines in a fully coherent way the templating molecule and linear regression approaches. A number of case studies show that the new Nano LEGO tool provides geometrical parameters on par with state-of-the-art composite wave function methods, but can be routinely applied to medium- to large-size molecules. The accuracy reached for structural parameters is mirrored on rotational constants that can be predicted with an average error within 0.2%.

Benchmark Structures and Conformational Landscapes of Amino Acids in the Gas Phase: A Joint Venture of Machine Learning, Quantum Chemistry, and Rotational Spectroscopy.

The accurate characterization of prototypical bricks of life can strongly benefit from the integration of high resolution spectroscopy and quantum mechanical computations. We have selected a number of representative amino acids (glycine, alanine, serine, cysteine, threonine, aspartic acid and asparagine) to validate a new computational setup rooted in quantum-chemical computations of increasing accuracy guided by machine learning tools. Together with low-lying energy minima, the barriers ruling their interconversion are evaluated in order to unravel possible fast relaxation paths. Vibrational and thermal effects are also included in order to estimate relative free energies at the temperature of interest in the experiment. The spectroscopic parameters of all the most stable conformers predicted by this computational strategy, which do not have low-energy relaxation paths available, closely match those of the species detected in microwave experiments. Together with their intrinsic interest, these accurate results represent ideal benchmarks for more approximate methods.

Integration of Quantum Chemistry, Statistical Mechanics, and Artificial Intelligence for Computational Spectroscopy: The UV-Vis Spectrum of TEMPO Radical in Different Solvents.

The ongoing integration of quantum chemistry, statistical mechanics, and artificial intelligence is paving the route toward more effective and accurate strategies for the investigation of the spectroscopic properties of medium-to-large size chromophores in condensed phases. In this context we are developing a novel workflow aimed at improving the generality, reliability, and ease of use of the available computational tools. In this paper we report our latest developments with specific reference to unsupervised atomistic simulations employing non periodic boundary conditions (NPBC) followed by clustering of the trajectories employing optimized feature spaces. Next accurate variational computations are performed for a representative point of each cluster, whereas intracluster fluctuations are taken into account by a cheap yet reliable perturbative approach. A number of methodological improvements have been introduced including, e.g., more realistic reaction field effects at the outer boundary of the simulation sphere, automatic definition of the feature space by continuous perception of solute-solvent interactions, full account of polarization and charge transfer in the first solvation shell, and inclusion of vibronic contributions. After its validation, this new approach has been applied to the challenging case of solvatochromic effects on the UV-vis spectra of a prototypical nitroxide radical (TEMPO) in different solvents. The reliability, effectiveness, and robustness of the new platform is demonstrated by the remarkable agreement with experiment of the results obtained through an unsupervised approach characterized by a strongly reduced computational cost as compared to that of conventional quantum mechanics and molecular mechanics models without any accuracy reduction.

Unsupervised search of low-lying conformers with spectroscopic accuracy: A two-step algorithm rooted into the island model evolutionary algorithm.

The fruitful interplay of high-resolution spectroscopy and quantum chemistry has a long history, especially in the field of small, semi-rigid molecules. However, in recent years, the targets of spectroscopic studies are shifting toward flexible molecules, characterized by a large number of closely spaced energy minima, all contributing to the overall spectrum. Here, artificial intelligence comes into play since it is at the basis of powerful unsupervised techniques for the exploration of soft degrees of freedom. Integration of such algorithms with a two-stage QM/QM' (Quantum Mechanical) exploration/refinement strategy driven by a user-friendly graphical interface is the topic of the present paper. We will address in particular: (i) the performances of different semi-empirical methods for the exploration step and (ii) the comparison between stochastic and meta-heuristic algorithms in achieving a cheap yet complete exploration of the conformational space for medium sized chromophores. As test cases, we choose three amino acids of increasing complexity, whose full conformer enumeration has been reached only very recently. Next, we show that systems in condensed phases can be treated at the same level and with the same efficiency when employing a polarizable continuum description of the solvent. Finally, the challenging issue represented by the vibrational circular dichroism spectra of some rhodium complexes with flexible ligands has been addressed, showing that our fully unsupervised approach leads to remarkable agreement with the experiment.

Molecular Perception for Visualization and Computation: The Proxima Library.

Proxima is a molecular perception library designed with a double purpose: to be used with immersive molecular viewers (thus providing any required feature not supported by third party libraries) and to be integrated in workflow managers thus providing the functionalities needed for the first steps of molecular modeling studies. It thus stands at the boundary between visualization and computation. The purpose of the present article is to provide a general introduction to the first release of Proxima, describe its most significant features, and highlight its performance by means of some case studies. The current version of Proxima is available for evaluation purposes at https://bitbucket.org/sns-smartlab/proxima/src/master/.

Chemical promenades: Exploring potential-energy surfaces with immersive virtual reality.

The virtual-reality framework AVATAR (Advanced Virtual Approach to Topological Analysis of Reactivity) for the immersive exploration of potential-energy landscapes is presented. AVATAR is based on modern consumer-grade virtual-reality technology and builds on two key concepts: (a) the reduction of the dimensionality of the potential-energy surface to two process-tailored, physically meaningful generalized coordinates, and (b) the analogy between the evolution of a chemical process and a pathway through valleys (potential wells) and mountain passes (saddle points) of the associated potential energy landscape. Examples including the discovery of competitive reaction paths in simple A + BC collisional systems and the interconversion between conformers in ring-puckering motions of flexible rings highlight the innovation potential that augmented and virtual reality convey for teaching, training, and supporting research in chemistry.