LAPSE:2024.0197
Published Article
LAPSE:2024.0197
Exploring Partial Structural Disorder in Anhydrous Paraxanthine through Combined Experiment, Solid-State Computational Modelling, and Molecular Docking
Jolanta Natalia Latosińska, Magdalena Latosińska, Janez Seliger, Veselko Žagar
February 10, 2024
Paraxanthine (PX), a major metabolite of caffeine, a protective agent against Alzheimer’s and Parkinson’s disease, and a promising drug for the treatment of post-COVID 2019 anosmia and ageusia, has been studied in the solid state and protein−ligand complex. Partial disorder in PX, caused by the methyl group at the N(7) position, has been modelled and discussed. The relationship between the unusual structural disorder and the propensity to form a specific system of non-covalent bonds was analyzed. Three 1H-14N NMR-NQR (nuclear magnetic resonance−nuclear quadrupole resonance) experimental techniques were used, namely multiple frequency sweeps, Larmor frequency scanning, and the two-frequency irradiation, followed by solid-state computational modelling (density functional theory, supplemented by quantum theory of atoms in molecules, 3D Hirshfeld surfaces, and reduced density gradient), and molecular docking approaches. New quantitative methods for estimating changes in the global pattern of interactions under the influence of rotation of the methyl group in N(7) based on the Pompeiu−Hausdorff and Bhattacharayya metrics and the Wasserstein distance have been proposed and applied. A spectrum consisting of 12 lines, indicating the presence of 4 chemically inequivalent nitrogen sites in the PX molecule, was recorded, and the lines’ assignment to particular sites was made. The influence of the methyl rotation on the eigenvalues and eigenvectors of the electric field gradient tensor, NQR parameters, and resonance line positions was modelled in the solid (GGA/RPBE, m-GGA/RSCAN) and cluster (Minnesota M062X hybrid). Three factors have been found to determine structural disorder in PX: larger crystal voids near the methyl at N(7) than at N(1) (opening the path for the disorder), hyperconjugation strongly affecting the density distribution in the five-membered ring, and the involvement of the methyl group at N(7) in many non-covalent bonds that intercept (capture) subsequent jumping protons. The Pompeiu−Hausdorff and Bhattacharayya metrics and the Wasserstein distance confirmed the changes in the distribution and strength of non-covalent interactions throughout the molecule as a result of methyl rotation. This effect is clearly visible regardless of the type of metric, and its order of magnitude is consistent with the modulation effect of the NQR spectra (experimental and calculated). Through molecular docking, it was discovered that the PX moiety in protein−ligand complexes adopt the same methyl group conformation at N(7) as in the solid state. It was found that the cooperation−competition between the C-H⋯O hydrogen bonds and C-H⋯H-C dispersion interactions is the crucial factor that impedes methyl rotation and induces structural disorder, as well as being an important factor in the formation of the protein−ligand complexes.
Keywords
binding mode of paraxanthine with A2A receptor, disorder, hydrogen bonds, methyl rotation, molecular docking, molecular dynamics, non-covalent interactions, paraxanthine
Suggested Citation
Latosińska JN, Latosińska M, Seliger J, Žagar V. Exploring Partial Structural Disorder in Anhydrous Paraxanthine through Combined Experiment, Solid-State Computational Modelling, and Molecular Docking. (2024). LAPSE:2024.0197
Author Affiliations
Latosińska JN: Faculty of Physics, Adam Mickiewicz University, Uniwersytetu Poznańskiego 2, 61-614 Poznań, Poland [ORCID]
Latosińska M: Faculty of Physics, Adam Mickiewicz University, Uniwersytetu Poznańskiego 2, 61-614 Poznań, Poland
Seliger J: Faculty of Mathematics and Physics, University of Ljubljana, Jadranska 19, 1000 Ljubljana, Slovenia [ORCID]
Žagar V: “Jožef Stefan” Institute, Jamova 39, 1000 Ljubljana, Slovenia
Journal Name
Processes
Volume
11
Issue
9
First Page
2740
Year
2023
Publication Date
2023-09-14
Published Version
ISSN
2227-9717
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PII: pr11092740, Publication Type: Journal Article
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LAPSE:2024.0197
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doi:10.3390/pr11092740
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Feb 10, 2024
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