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Molecular Sensitivity and Weak Interactions

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Computational and Theoretical Chemistry".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 17092

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Prof. Dr. Irena Majerz

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Faculty of Pharmacy, Wroclaw Medical University, Borowska 211a, 50-556 Wroclaw, Poland
Interests: hydrogen bond; weak interaction; molecular modeling; crystal structure; electron density; aromaticity

Special Issue Information

Dear Colleagues,

Weak interactions cover a wide range of different effects, including typical and improper hydrogen bond, halogen bond, charge transfer interactions, van der Waals, stacking, dispersion, steric, and many other interactions specific to individual molecular systems. The variety of the weak interactions and their common occurrence determines their significance. Due to their varied strength, only some of them can be investigated using experimental methods. Computational methods allow for a deeper understanding and interpretation, and in the case of the weakest interactions, they are the only accessible research tool. Molecules are sensitive to the molecular environment and strong intermolecular interactions. In the case of simple molecules, the sensitivity to interactions is manifested by changes in the electron density and related parameters such as aromaticity, electron delocalization or magnetically induced currents. Particularly noteworthy is the influence of weak interactions which, despite their negligible strength, can modify the interacting molecules. Weak cooperative interactions can modify not only the electron density, but also the geometry of large molecules. Sensitivity of molecular properties to weak interactions is important in many fields of science, including biological recognition, protein folding, ligand binding, crystal engineering, etc. The Special Issue is open to all papers on the molecular sensitivity to weak interactions.

Prof. Irena Majerz
Guest Editor

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Keywords

Interaction
Hydrogen bond
van der Waals interaction
Stacking
Dispersion
Halogen bond
Steric effect
Theoretical calculations
Molecular modeling

Published Papers (9 papers)

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Research

24 pages, 20032 KiB

Open AccessArticle

Prototropy, Intramolecular Interactions, Electron Delocalization, and Physicochemical Properties of 1,8-dihydroxy-9-anthrone—DFT-D3 Study of Substituent Effects

by Małgorzata Szymańska and Irena Majerz

Molecules 2023, 28(1), 344; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28010344 - 01 Jan 2023

Viewed by 1007

Abstract

1,8-dihydroxy-9-anthrone are tricyclic compounds with a ketone group in the middle ring and two hydroxyl groups substituted in the side-aromatic rings what results in formation of two intramolecular hydrogen bonds in which the oxygen atom from the ketone group is the proton acceptor. 1,8-dihydroxy-9-anthrones in which intramolecular proton transfer between C10 and CO in the middle ring occurs, can exist in a tautomeric keto-enol equilibrium. For anthralin, the most important representative of this group, this equilibrium has been studied previously, but it has not been studied for its derivatives. Substituents in the middle ring change the geometry of 1,8-dihydroxy-9-anthrones so they are also expected to affect the keto-enol equilibrium. It is also important to study the effect of intramolecular hydrogen bonds on the structure of both tautomeric forms. It was found that the nature of the substituent in the middle ring could affect the antioxidant properties of the investigated compound. Full article

(This article belongs to the Special Issue Molecular Sensitivity and Weak Interactions)

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17 pages, 3643 KiB

Open AccessArticle

Impact of Dispersion Force Schemes on Liquid Systems: Comparing Efficiency and Drawbacks for Well-Targeted Test Cases

by Evelyne Martin, Iréné Bérenger Amiehe Essomba, Kana Ishisone, Mauro Boero, Guido Ori and Carlo Massobrio

Molecules 2022, 27(24), 9034; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27249034 - 18 Dec 2022

Cited by 1 | Viewed by 1144

Abstract

First-principles molecular dynamics (FPMD) calculations were performed on liquid GeSe₄ with the aim of inferring the impact of dispersion (van der Waals, vdW) forces on the structural properties. Different expressions for the dispersion forces were employed, allowing us to draw conclusions on their performances in a comparative fashion. These results supersede previous FPMD calculations obtained in smaller systems and shorter time trajectories by providing data of unprecedented accuracy. We obtained a substantial agreement with experiments for the structure factor regardless of the vdW scheme employed. This objective was achieved by using (in addition to FPMD with no dispersion forces) a selection of vdW schemes available within density functional theory. The first two are due to Grimme, D2 and D3, and the third one is devised within the so-called maximally localized Wannier functions approach (MLWF). D3 results feature a sizeable disagreement in real space with D2 and MLWF in terms of the partial and total pair correlation functions as well as the coordination numbers. More strikingly, total and partial structure factors calculated with D3 exhibit an unexpected sharp increase at low k. This peculiarity goes along with large void regions within the network, standing for a phase separation of indecipherable physical meaning. In view of these findings, further evidence of unconventional structural properties found by employing D3 is presented by relying on results obtained for a complex ionic liquid supported on a solid surface. The novelty of our study is multifold: new, reliable FPMD data for a prototypical disordered network system, convincing agreement with experimental data and assessment of the impact of dispersion forces, with emphasis on the intriguing behavior of one specific recipe and the discovery of common structural features shared by drastically dissimilar physical systems when the D3 vdW scheme is employed. Full article

(This article belongs to the Special Issue Molecular Sensitivity and Weak Interactions)

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18 pages, 4029 KiB

Open AccessArticle

X-ray Structures and Computational Studies of Two Bioactive 2-(Adamantane-1-carbonyl)-N-substituted Hydrazine-1-carbothioamides

by Lamya H. Al-Wahaibi, Kowsalya Alagappan, Olivier Blacque, Ahmed A. B. Mohamed, Hanan M. Hassan, María Judith Percino, Ali A. El-Emam and Subbiah Thamotharan

Molecules 2022, 27(23), 8425; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27238425 - 01 Dec 2022

Cited by 1 | Viewed by 1457

Abstract

Two biologically active adamantane-linked hydrazine-1-carbothioamide derivatives, namely 2-(adamantane-1-carbonyl)-N-(tert-butyl)hydrazine-1-carbothioamide) 1 and 2-(adamantane-1-carbonyl)-N-cyclohexylhydrazine-1-carbothioamide 2, have been synthesized. X-ray analysis was conducted to study the effect of the t-butyl and cyclohexyl moieties on the intermolecular interactions and conformation of the molecules in the solid state. X-ray analysis reveals that compound 1 exhibits folded conformation, whereas compound 2 adopts extended conformation. The Hirshfeld surface analysis indicates that the contributions of the major intercontacts involved in the stabilization of the crystal structures do not change much as a result of the t-butyl and cyclohexyl moieties. However, the presence and absence of these contacts is revealed by the 2D-fingerprint plots. The CLP–Pixel method was used to identify the energetically significant molecular dimers. These dimers are stabilized by different types of intermolecular interactions such as N–H···S, N–H···O, C–H···S, C–H···O, H–H bonding and C–H···π interactions. The strength of these interactions was quantified by using the QTAIM approach. The results suggest that N–H···O interaction is found to be stronger among other interactions. The in vitro assay suggests that both compounds 1 and 2 exhibit urease inhibition potential, and these compounds also display moderate antiproliferative activities. Molecular docking analysis shows the key interaction between urease enzyme and title compounds. Full article

(This article belongs to the Special Issue Molecular Sensitivity and Weak Interactions)

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27 pages, 6214 KiB

Open AccessArticle

Weak Noncovalent Interactions in Three Closely Related Adamantane-Linked 1,2,4-Triazole N-Mannich Bases: Insights from Energy Frameworks, Hirshfeld Surface Analysis, In Silico 11β-HSD1 Molecular Docking and ADMET Prediction

by Lamya H. Al-Wahaibi, Mario A. Macías, Olivier Blacque, Luke S. Zondagh, Jacques Joubert, Subbiah Thamotharan, María Judith Percino, Ahmed A. B. Mohamed and Ali A. El-Emam

Molecules 2022, 27(21), 7403; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27217403 - 31 Oct 2022

Cited by 1 | Viewed by 1499

Abstract

Structural analysis and docking studies of three adamantane-linked 1,2,4-triazole N-Mannich bases (1–3) are presented. Compounds 1, 2 and 3 crystallized in the monoclinic P2₁/c, P2₁ and P2₁/n space groups, respectively. Crystal packing of 1 was stabilized by intermolecular C-H⋯O interactions, whereas compounds 2 and 3 were stabilized through intermolecular C-H⋯N, C-H⋯S and C-H⋯π interactions. The energy frameworks for crystal structures of 1–3 were described. The substituent effect on the intermolecular interactions and their contributions were described on the basis of Hirshfeld surface analyses. The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibition potential, pharmacokinetic and toxicity profiles of compounds 1–3 were determined using in silico techniques. Molecular docking of the compounds into the 11β-HSD1 active site showed comparable binding affinity scores (−7.50 to −8.92 kcal/mol) to the 11β-HSD1 co-crystallized ligand 4YQ (−8.48 kcal/mol, 11β-HSD1 IC₅₀ = 9.9 nM). The compounds interacted with key active site residues, namely Ser170 and Tyr183, via strong hydrogen bond interactions. The predicted pharmacokinetic and toxicity profiles of the compounds were assessed, and were found to exhibit excellent ADMET potential. Full article

(This article belongs to the Special Issue Molecular Sensitivity and Weak Interactions)

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24 pages, 7186 KiB

Open AccessArticle

Revealing Intra- and Intermolecular Interactions Determining Physico-Chemical Features of Selected Quinolone Carboxylic Acid Derivatives

by Kamil Wojtkowiak, Aneta Jezierska and Jarosław J. Panek

Molecules 2022, 27(7), 2299; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27072299 - 01 Apr 2022

Viewed by 1686

Abstract

The intra- and intermolecular interactions of selected quinolone carboxylic acid derivatives were studied in monomers, dimers and crystals. The investigated compounds are well-recognized as medicines or as bases for further studies in drug design. We employed density functional theory (DFT) in its classical formulation to develop gas-phase and solvent reaction field (PCM) models describing geometric, energetic and electronic structure parameters for monomers and dimers. The electronic structure was investigated based on the atoms in molecules (AIM) and natural bond orbital (NBO) theories. Special attention was devoted to the intramolecular hydrogen bonds (HB) present in the investigated compounds. The characterization of energy components was performed using symmetry-adapted perturbation theory (SAPT). Finally, the time-evolution methods of Car–Parrinello molecular dynamics (CPMD) and path integral molecular dynamics (PIMD) were employed to describe the hydrogen bond dynamics as well as the spectroscopic signatures. The vibrational features of the O-H stretching were studied using Fourier transformation of the autocorrelation function of atomic velocity. The inclusion of quantum nuclear effects provided an accurate depiction of the bridged proton delocalization. The CPMD and PIMD simulations were carried out in the gas and crystalline phases. It was found that the polar environment enhances the strength of the intramolecular hydrogen bonds. The SAPT analysis revealed that the dispersive forces are decisive factors in the intermolecular interactions. In the electronic ground state, the proton-transfer phenomena are not favourable. The CPMD results showed generally that the bridged proton is localized at the donor side, with possible proton-sharing events in the solid-phase simulation of stronger hydrogen bridges. However, the PIMD enabled the quantitative estimation of the quantum effects inclusion—the proton position was moved towards the bridge midpoint, but no qualitative changes were detected. It was found that the interatomic distance between the donor and acceptor atoms was shortened and that the bridged proton was strongly delocalized. Full article

(This article belongs to the Special Issue Molecular Sensitivity and Weak Interactions)

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19 pages, 2230 KiB

Open AccessArticle

Exploring Intra- and Intermolecular Interactions in Selected N-Oxides—The Role of Hydrogen Bonds

by Aneta Jezierska, Jarosław J. Panek, Kacper Błaziak, Kamil Raczyński and Aleksander Koll

Molecules 2022, 27(3), 792; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27030792 - 25 Jan 2022

Cited by 4 | Viewed by 2414

Abstract

Intra- and intermolecular interactions have been explored in selected N-oxide derivatives: 2-(N,N-dimethylamino-N-oxymethyl)-4,6-dimethylphenyl (1) and 5,5’-dibromo-3-diethylaminomethyl-2,2’-biphenol N-oxide (2). Both compounds possess intramolecular hydrogen bonding, which is classified as moderate in 1 and strong in 2, and resonance-assisted in both cases. Density Functional Theory (DFT) in its classical formulation as well as Time-Dependent extension (TD-DFT) were employed to study proton transfer phenomena. The simulations were performed in the gas phase and with implicit and explicit solvation models. The obtained structures of the studied N-oxides were compared with experimental data available. The proton reaction path was investigated using scan with an optimization method, and water molecule reorientation in the monohydrate of 1 was found upon the proton scan progress. It was found that spontaneous proton transfer phenomenon cannot occur in the electronic ground state of the compound 1. An opposite situation was noticed for the compound 2. The changes of nucleophilicity and electrophilicity upon the bridged proton migration were analyzed on the basis of Fukui functions in the case of 1. The interaction energy decomposition of dimers and microsolvation models was investigated using Symmetry-Adapted Perturbation Theory (SAPT). The simulations were performed in both phases to introduce polar environment influence on the interaction energies. The SAPT study showed rather minor role of induction in the formation of homodimers. However, it is worth noticing that the same induction term is responsible for the preference of water molecules’ interaction with N-oxide hydrogen bond acceptor atoms in the microsolvation study. The Natural Bond Orbital (NBO) analysis was performed for the complexes with water to investigate the charge flow upon the polar environment introduction. Finally, the TD-DFT was applied for isolated molecules as well as for microsolvation models showing that the presence of solvent affects excited states, especially when the N-oxide acceptor atom is microsolvated. Full article

(This article belongs to the Special Issue Molecular Sensitivity and Weak Interactions)

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13 pages, 2358 KiB

Open AccessEditor’s ChoiceArticle

Comparison of Proton Acceptor and Proton Donor Properties of H₂O and H₂O₂ in Organic Crystals of Drug-like Compounds: Peroxosolvates vs. Crystallohydrates

by Mikhail V. Vener, Andrei V. Churakov, Alexander P. Voronin, Olga D. Parashchuk, Sergei V. Artobolevskii, Oleg A. Alatortsev, Denis E. Makhrov, Alexander G. Medvedev and Aleksander Filarowski

Molecules 2022, 27(3), 717; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27030717 - 22 Jan 2022

Cited by 11 | Viewed by 2131

Abstract

Two new peroxosolvates of drug-like compounds were synthesized and studied by a combination of X-ray crystallographic, Raman spectroscopic methods, and periodic DFT computations. The enthalpies of H-bonds formed by hydrogen peroxide (H₂O₂) as a donor and an acceptor of protons were compared with the enthalpies of analogous H-bonds formed by water (H₂O) in isomorphic (isostructural) hydrates. The enthalpies of H-bonds formed by H₂O₂ as a proton donor turned out to be higher than the values of the corresponding H-bonds formed by H₂O. In the case of H₂O₂ as a proton acceptor in H-bonds, the ratio appeared reversed. The neutral O∙∙∙H-O/O∙∙∙H-N bonds formed by the lone electron pair of the oxygen atom of water were the strongest H-bonds in the considered crystals. In the paper, it was found out that the low-frequency Raman spectra of isomorphous crystalline hydrate and peroxosolvate of N-(5-Nitro-2-furfurylidene)-1-aminohydantoin are similar. As for the isostructural hydrate and peroxosolvate of the salt of protonated 2-amino-nicotinic acid and maleic acid monoanion, the Raman spectra are different. Full article

(This article belongs to the Special Issue Molecular Sensitivity and Weak Interactions)

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16 pages, 1381 KiB

Open AccessArticle

Matrix Isolation FTIR and Theoretical Study of Weakly Bound Complexes of Isocyanic Acid with Nitrogen

by Justyna Krupa, Maria Wierzejewska and Jan Lundell

Molecules 2022, 27(2), 495; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27020495 - 13 Jan 2022

Cited by 5 | Viewed by 2392

Abstract

Weak complexes of isocyanic acid (HNCO) with nitrogen were studied computationally employing MP2, B2PLYPD3 and B3LYPD3 methods and experimentally by FTIR matrix isolation technique. The results show that HNCO interacts specifically with N₂. For the 1:1 stoichiometry, three stable minima were located on the potential energy surface. The most stable of them involves a weak, almost linear hydrogen bond from the NH group of the acid molecule to nitrogen molecule lone pair. Two other structures are bound by van der Waals interactions of N⋯N and C⋯N types. The 1:2 and 2:1 HNCO complexes with nitrogen were computationally tracked as well. Similar types of interactions as in the 1:1 complexes were found in the case of the higher stoichiometry complexes. Analysis of the HNCO/N₂/Ar spectra after deposition indicates that the 1:1 hydrogen-bonded complex is prevalent in argon matrices with a small amount of the van der Waals structures also present. Upon annealing, complexes of the 1:2 and 2:1 stoichiometry were detected as well. Full article

(This article belongs to the Special Issue Molecular Sensitivity and Weak Interactions)

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14 pages, 3774 KiB

Open AccessArticle

Molecular Mechanisms on the Selectivity Enhancement of Ascorbic Acid, Dopamine, and Uric Acid by Serine Oligomers Decoration on Graphene Oxide: A Molecular Dynamics Study

by Threrawee Sanglaow, Pattanan Oungkanitanon, Piyapong Asanithi and Thana Sutthibutpong

Molecules 2021, 26(10), 2876; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26102876 - 13 May 2021

Cited by 3 | Viewed by 2199

Abstract

The selectivity in the simultaneous detection of ascorbic acid (AA), dopamine (DA), and uric acid (UA) has been an open problem in the biosensing field. Many surface modification methods were carried out for glassy carbon electrodes (GCE), including the use of graphene oxide and amino acids as a selective layer. In this work, molecular dynamics (MD) simulations were performed to investigate the role of serine oligomers on the selectivity of the AA, DA, and UA analytes. Our models consisted of a graphene oxide (GO) sheet under a solvent environment. Serine tetramers were added into the simulation box and were adsorbed on the GO surface. Then, the adsorption of each analyte on the mixed surface was monitored from MD trajectories. It was found that the adsorption of AA was preferred by serine oligomers due to the largest number of hydrogen-bond forming functional groups of AA, causing a 10-fold increase of hydrogen bonds by the tetraserine adsorption layer. UA was the least preferred due to its highest aromaticity. Finally, the role of hydrogen bonds on the electron transfer selectivity of biosensors was discussed with some previous studies. AA radicals received electrons from serine through hydrogen bonds that promoted oxidation reaction and caused the negative shifts and separation of the oxidation potential in experiments, as DA and UA were less affected by serine. Agreement of the in vitro and in silico results could lead to other in silico designs of selective layers to detect other types of analyte molecules. Full article

(This article belongs to the Special Issue Molecular Sensitivity and Weak Interactions)

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