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

Aug 6, 2026

A combined experimental and theoretical study investigates 4-fluoro-threonine, the only naturally occurring fluorinated amino acid. Fluorination of the methyl group increases conformational complexity relative to threonine and enables a detailed characterization of the conformational landscape, including inter-conversion pathways between conformers. Thirteen stable low-energy minima are identified, and twelve conformers are experimentally characterized using a strategy that merges multi-level quantum chemical calculations with machine-learning principles. Analysis of intra-molecular interactions supports accurate modeling of fluorine-substitution effects in biomolecules.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Abstract

Introduction

Background on fluorinated molecules and fluorine effects

Relevance of fluorinated α-amino acids and 4-fluoro-threonine

Approach: gas-phase rotational spectroscopy, quantum chemistry, and machine learning

Chemistry—A EuropeanJournal Research Article [doi.org/10.1002/chem.202203990](doi.org/10.1002/chem.202203990) [www.chemeurj.org](www.chemeurj.org) Bringing Machine-Learning Enhanced Quantum Chemistry and Microwave Spectroscopy to Conformational Landscape Exploration: the Paradigmatic Case of 4-Fluoro-Threonine V. Barone,*[a] M. Fusè,[a] R. Aguado,[b] S. Potenti,[a, c] I. León,[b] E. R. Alonso,[b] S. Mata,[b] F. Lazzari,[a] G. Mancini,[a] L. Spada,[a] A. Gualandi,[c] P. G. Cozzi,[c] C. Puzzarini,*[c] and J. L. Alonso*[b] |
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 equili- |
brium 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 biomole- | | | --- | --- | --- | | | cules. | | Introduction Fluorinated organic molecules play an important role in medicinal chemistry. [1,2] Before the Covid-19 pandemic, the most prescribed drug in the world was atorvastatin (Lipitor), which features a fluorinated phenyl substituent. Moreover, nearly half of the new small molecule drugs approved by the US Food and Drug Administration in 2018 contained a fluorine atom.[3] Replacement of a hydrogen by the similarly sized fluorine atom tends to have a negligible impact on steric properties and molecular shape, while the vastly different electronic properties of fluorine can have profound effects on binding energy, reactivity, and relative energy of corresponding [a] Prof. Dr. V. Barone, Dr. M. Fusè, Dr. S. Potenti, F. Lazzari, Dr. G. Mancini, Dr. L. Spada SMART Laboratory, Scuola Normale Superiore di Pisa, piazza dei Cavalieri 7, 56126 Pisa, Italy E-mail: [vincenzo.barone@sns.it](vincenzo.barone@sns.it) [b] R. Aguado, Dr. I. León, E. R. Alonso, S. Mata, Prof. Dr. J. L. Alonso Grupo de Espectroscopia Molecular (GEM), Edificio Quifima, Laboratorios de Espectroscopia y Bioespectroscopia Parque Cientifico UVa, Universidad de Valladolid, 47005 Valladolid, Spain [E-mail: jlalonso@qf.uva.es](E-mail: jlalonso@qf.uva.es) [c] Dr. S. Potenti, Dr. A. Gualandi, Prof. Dr. P. G. Cozzi, Prof. Dr. C. Puzzarini Dipartimento di “Chimica Giacomo Ciamician”, University of Bologna, via F. Selmi 2, 40126, Bologna, Italy E-mail: [cristina.puzzarini@unibo.it](cristina.puzzarini@unibo.it) Supporting information for this article is available on the WWW under [https://doi.org/10.1002/chem.202203990](https://doi.org/10.1002/chem.202203990) © 2023 The Authors. Chemistry-A European Journal published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. conformers on the potential energy landscape. [1,4] For the structural and physical chemist, conformers of such fluorinated compounds tend to have geometries qualitatively similar to those of the parent compounds, although the introduction of the fluorine atom can lead to a breaking of equivalence of positions in the parent compound, which leads to a more complicated conformat

FAQs

What molecule is studied and why is it significant?

The study focuses on 4-fluoro-threonine, the only naturally occurring fluorinated amino acid, obtained by fluorination of threonine’s terminal methyl group.

How does fluorination affect the conformational landscape?

Fluorination of the methyl group increases conformational complexity, producing many stable low-energy minima and a congested rotational spectrum.

How are conformers assigned despite the complexity of the spectrum?

Conformer assignments are achieved using a strategy combining several levels of quantum chemical calculations with machine-learning principles, enabling characterization of 12 out of 13 stable low-energy minima.

Aug 6, 2026

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