Bringing Machine‐Learning Enhanced Quantum Chemistry and Microwave Spectroscopy to Conformational Landscape Exploration: the Paradigmatic Case of 4‐Fluoro‐Threonine

Abstract

A combined experimental and theoretical study has been carried out on 4‐fluoro‐threonine, the only naturally occurring fluorinated amino acid. Fluorination of the methyl group significantly increases the conformational complexity with respect to the parent amino acid threonine. The conformational landscape has been characterized in great detail, with special attention given to the inter‐conversion pathways between different conformers. This led to the identification of 13 stable low‐energy minima. The equilibrium population of so many conformers produces a very complicated and congested rotational spectrum that could be assigned through a strategy that combines several levels of quantum chemical calculations with the principles of machine learning. Twelve conformers out of 13 could be experimentally characterized. The results obtained from the analysis of the intra‐molecular interactions can be exploited to accurately model fluorine‐substitution effects in biomolecules.

Accurate Structures and Spectroscopic Parameters of Phenylalanine and Tyrosine in the Gas Phase: A Joint Venture of DFT and Composite Wave-Function Methods

“… 92 Replacement of conventional methods by the explicitly correlated (F12) variants 93 , 94 leads to our current standard version of the approach, which is referred to as junChS-F12. 42 , 58 , 60 Comparison with the most accurate results available for a panel of representative noncovalent complexes provided an average absolute error smaller than 10 cm –1 . 41 , 42 , 60 …”

“…In particular, the CBS extrapolation by the standard n –3 two-point formula employs MP2/jun-cc-pV­(X+d)­Z energies with X = T and Q, whereas the CV contribution is incorporated as the difference between all-electron (ae) and fc MP2 calculations, both with the cc-pCVW­(T+d)­Z basis set . Replacement of conventional methods by the explicitly correlated (F12) variants , leads to our current standard version of the approach, which is referred to as junChS-F12. ,, Comparison with the most accurate results available for a panel of representative noncovalent complexes provided an average absolute error smaller than 10 cm –1 . ,, …”

“…This procedure has been recently validated for several amino acids containing polar side chains. − Here we tackle the problem of aromatic side chains analyzing both the rotational and vibrational spectra of the prototypical phenylalanine and tyrosine amino acids. In fact, previous studies of these amino acids employed QC methods of limited accuracy, payed marginal attention to the geometrical parameters and neglected vibrational corrections beyond the standard rigid rotor harmonic oscillator (RRHO) model.…”

Computational Protocol for the Identification of Candidates for Radioastronomical Detection and Its Application to the C3H3NO Family of Isomers

“…The selection of initial structures to be considered is left to the user, but in this case, Sci-Finder was employed to obtain a large number of initial structures. An automatic procedure based on genetic algorithms guiding semi-empirical methods [ 72 , 73 , 74 ] is currently under development.…”

Toward the Detection of Cyanoketene in the Interstellar Medium: New Hints from Quantum Chemistry and Rotational Spectroscopy

“…In particular, the CBS extrapolation by the standard n –3 two-point formula employs MP2/jun-cc-pV­(X+d)­Z energies with X = T and Q, whereas the CV contribution is incorporated as the difference between all-electron (ae) and fc MP2 calculations, both with the cc-pCVW­(T+d)­Z basis set . Replacement of conventional methods by the explicitly correlated (F12) variants , leads to our current standard version of the approach, which is referred to as junChS-F12. − A comparison to the most accurate results available for reaction energies and activation barriers ,, showed that junChS-F12 energy evaluations at rDSD optimized geometries provide average absolute errors of the order of 1 kJ mol –1 . Therefore, this approach was employed for all of the stationary points in conjunction with anharmonic zero-point vibrational energy corrections computed in the framework of the second-order vibrational perturbation theory employing rDSD anharmonic force fields.…”