Mining anion–aromatic interactions in the Protein Data Bank

Kuzniak-Glanowska, Emilia; Glanowski, Michał; Kurczab, Rafał; Bojarski, Andrzej J.; Podgajny, Robert

doi:10.1039/d2sc00763k

Cited by 9 publications

(11 citation statements)

References 103 publications

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“…It is interesting that the structure displays bifurcated N–H···O interactions in which the nitrogen atom of HL ’s amino group functions as a hydrogen bond donor with two separate oxygen acceptors while O5 from the nitrate ion acts as a bifurcated acceptor for two distinct donors from HL (N3 and C18) (see Figure ). Furthermore, hydrogen bonds and π···π (with a centroid···centroid separation of 3.787 Å) and anion···π interactions , (with a centroid···O separation of 3.796 Å) between the nitrate ion and the amino group of HL generate the third dimension along the b -axis (see Figure ). The presence of the nitrate anion is particularly significant in the expansion and stability of this supramolecular network, as shown by the structure of this complex.…”

Section: Resultsmentioning

confidence: 99%

Biological Activity of Two Anticancer Pt Complexes with a Cyclohexylglycine Ligand against a Colon Cancer Cell Line: Theoretical and Experimental Study

et al. 2022

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Because of their extraordinary ability to disrupt the natural structure of nucleic acids, metal complexes could be used in cancer therapy. In this study, cyclohexylglycine (HL) as a ligand and two new Pt complexes, [Pt(NH 3 ) 2 (L)]NO 3 (1) and [Pt(bipy)(L)]NO 3 (2), were synthesized and characterized by elemental analysis, LC-MS, UV−vis spectrometry, FT-IR, 1 H NMR spectroscopy, 13 C NMR spectroscopy, 195 Pt NMR spectroscopy, HPLC analysis, and single-crystal X-ray diffraction. Complex 2 crystallized in the orthorhombic Pbca space group, and density functional theory (DFT) was used to describe its structural parameters were described in detail. These complexes can be classified as oral medications and drug-like molecules based on a comparison of their absorption, distribution, metabolism, and excretion assessment. Quantum chemical descriptors (QCDs) were determined using DFT calculations to predict the tendency of DNA to approach these complexes. During the determination of the function of the metallodrug in DNA binding, the fluorescence data indicated that static quenching took place for all ligands and complexes with higher DNA binding affinity. CD and isothermal absorption studies indicate the presence of electrostatic and groove binding for the amine derivative and that DNA binds with the bipy moiety via groove binding. Furthermore, the interaction modes were determined using molecular docking to investigate the binding of these compounds with the target DNA molecule. According to docking investigations, binding energies of −5.7, −11.56, and −10.00 kcal/mol for HL and complexes 1 and 2, respectively, indicate partially electrostatic and groove binding. The anticancer activities of the Pt(II) complexes were tested against the HCT116 human colon cancer cell line, with IC 50 values of 35.51 and 51.33 μM for 1 and 2, respectively, after 72 h. These values show that the inhibitory effect of complex 1 was better than those of 2 and carboplatin (IC 50 = 51.94 μM).

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Section: Resultsmentioning

confidence: 99%

Biological Activity of Two Anticancer Pt Complexes with a Cyclohexylglycine Ligand against a Colon Cancer Cell Line: Theoretical and Experimental Study

et al. 2022

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“…In addition to the anion interacting with the π region of the aromatic rings, its interaction with the edge of the ring is also frequent in proteins and is referred to as the anion–aromatic or anion–quadrupole interaction (Figure D). − The distance of ≤4.5 Å between the ring center and anion implies a favorable interaction that is driven by electrostatics. , The calculated strength of this edgewise interaction can be up to −8.0 kcal mol –1 . , A PDB survey indicates that aromatic residues prefer an anion–quadrupole more than an anion−π interaction, possibly because of the unfavorable interaction between these electron-rich moieties . Of all of the aromatic residues interacting with anions, 62.9% of His, 55.3% of Tyr, 46.4% of Trp, and 27% of Phe residues form the anion–quadrupole interaction . On the contrary, only up to ∼8% of these residues interact with anions via the π region to form an anion−π interaction .…”

Section: Anion···π and Anion–aromatic Interactionsmentioning

confidence: 99%

The Realm of Unconventional Noncovalent Interactions in Proteins: Their Significance in Structure and Function

Adhav

Saikrishnan

2023

ACS Omega

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Proteins and their assemblies are fundamental for living cells to function. Their complex three-dimensional architecture and its stability are attributed to the combined effect of various noncovalent interactions. It is critical to scrutinize these noncovalent interactions to understand their role in the energy landscape in folding, catalysis, and molecular recognition. This Review presents a comprehensive summary of unconventional noncovalent interactions, beyond conventional hydrogen bonds and hydrophobic interactions, which have gained prominence over the past decade. The noncovalent interactions discussed include low-barrier hydrogen bonds, C5 hydrogen bonds, C–H···π interactions, sulfur-mediated hydrogen bonds, n → π* interactions, London dispersion interactions, halogen bonds, chalcogen bonds, and tetrel bonds. This Review focuses on their chemical nature, interaction strength, and geometrical parameters obtained from X-ray crystallography, spectroscopy, bioinformatics, and computational chemistry. Also highlighted are their occurrence in proteins or their complexes and recent advances made toward understanding their role in biomolecular structure and function. Probing the chemical diversity of these interactions, we determined that the variable frequency of occurrence in proteins and the ability to synergize with one another are important not only for ab initio structure prediction but also to design proteins with new functionalities. A better understanding of these interactions will promote their utilization in designing and engineering ligands with potential therapeutic value.

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“…with the anion localized over the ring, or ‘peripheral’, i.e. with the anion close to the ring plane or above the ring substituents ( 55 ). This study confirmed the abundance of anion…aromatic interactions in basically all investigated systems and showed that nucleobases and ligands exhibit a considerable preference for ‘canonical’ anion…π contacts.…”

Section: Introductionmentioning

confidence: 99%

“…In the context of RNA, when the current view in chemistry was that forces between anions and the seemingly electron-rich π-system of an aromatic ring could be repulsive ( 56 ), it was debated whether such an interaction would be a stabilizing or a merely tolerated short contact ( 36 ). Nowadays, the anion…π stacking contact between phosphate and uracil is known to occur in 3- and 4-nt U-turns ( 29 , 36 , 57 ), and the contact between phosphate and guanine is described as a conserved and key feature of GNRA tetraloops (frequently occurring structural motifs, where N stands for any nucleobase and R stands for A or G) ( 29 , 55 ). In addition, by quantum mechanics (QM) calculations, this specific interaction between a phosphate and a guanine two residues upstream in the context of GNRA motifs has been estimated to be stabilizing by 3–4 kcal•mol −1 ( 58 ).…”

Section: Introductionmentioning

confidence: 99%

“…While the structural role of the phosphate…π stacking interactions in the RNA GNRA tetraloops is now recognized and studies are currently exploring the possibility of bolstering their stability by incorporation of a thiophosphate modification ( 60 , 61 ), a thorough structural characterization of phosphate-nucleobase anion…π stacking interactions in general in RNA molecules and a full understanding of their physico-chemical nature and strength are not yet available in literature. To fill this gap, in this contribution we have carried out a systematic search of ‘canonical’ anion…π phosphate–nucleobase stacking interactions, which are indeed the preferred type of anion…π interactions for RNA ( 55 ), in a high-resolution non-redundant database of RNA structures ( 62 ). More importantly, we complemented this survey with statistical and structural analyses and with a state-of-the-art static and dynamic energetic characterization.…”

Section: Introductionmentioning

confidence: 99%

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Occurrence and stability of anion–π interactions between phosphate and nucleobases in functional RNA molecules

Chawla

Kalra²,

Cao

et al. 2022

Nucleic Acids Research

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We present a systematic structural and energetic characterization of phosphate(OP)–nucleobase anion…π stacking interactions in RNAs. We observed OP–nucleobase stacking contacts in a variety of structural motifs other than regular helices and spanning broadly diverse sequence distances. Apart from the stacking between a phosphate and a guanine or a uracil two-residue upstream in specific U-turns, such interactions in RNA have been scarcely characterized to date. Our QM calculations showed an energy minimum at a distance between the OP atom and the nucleobase plane centroid slightly below 3 Å for all the nucleobases. By sliding the OP atom over the nucleobase plane we localized the optimal mutual positioning of the stacked moieties, corresponding to an energy minimum below -6 kcal•mol−1, for all the nucleobases, consistently with the projections of the OP atoms over the different π-rings we observed in experimental occurrences. We also found that the strength of the interaction clearly correlates with its electrostatic component, pointing to it as the most relevant contribution. Finally, as OP–uracil and OP–guanine interactions represent together 86% of the instances we detected, we also proved their stability under dynamic conditions in model systems simulated by state-of-the art DFT-MD calculations.

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Mining anion–aromatic interactions in the Protein Data Bank

Abstract: Mutual positioning and non-covalent interactions in anion-aromatic motifs are crucial for functional performance of biological systems. In this context, regular, comprehensive Protein Data Bank (PDB) screening that involves various scientific...

Cited by 9 publications

References 103 publications

Biological Activity of Two Anticancer Pt Complexes with a Cyclohexylglycine Ligand against a Colon Cancer Cell Line: Theoretical and Experimental Study

Biological Activity of Two Anticancer Pt Complexes with a Cyclohexylglycine Ligand against a Colon Cancer Cell Line: Theoretical and Experimental Study

The Realm of Unconventional Noncovalent Interactions in Proteins: Their Significance in Structure and Function

Occurrence and stability of anion–π interactions between phosphate and nucleobases in functional RNA molecules

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