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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: 31 May 2025 | Viewed by 12157

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Prof. Dr. Wim Buijs

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Process and Energy Department, Delft University of Technology (Retired), Delft, The Netherlands
Interests: molecular modeling; CO₂ capture; cannabinoids; catalysis; oxidation; industrial chemistry; renewables; teaching

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Dear Colleagues,

Thanks to the rise of computational power and decreasing cost of computers, computational chemistry has evolved to a tool that changes the way chemical research and teaching is carried out. A wide variety of methods and tools have become available which not only can improve our understanding of basic chemical concepts but also is applicable to real experimental problems in academic and industrial research. Nowadays properties of molecules and molecular ensembles can be determined with sufficient accuracy to be useful in limiting the amount of experimental work in catalysis, drug discovery, and the development of new materials. Among them are thermodynamic properties, spectroscopical properties, and reaction kinetics to mention just a few. Visualization plays an important role in many aspects and particularly in teaching. Computational chemistry has the potential to become the universal (visual) language, uniting the different descriptions of similar chemical phenomena in disciplines like physical chemistry, organic chemistry, inorganic chemistry and biochemistry, catalysis and biocatalysis, pharmacokinetics.

We welcome original articles and short communications, as well as a limited number of review articles, on new approaches and methods of computational chemistry for research and teaching. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on the website.

Prof. Dr. Wim Buijs
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

visualization
molecular mechanics
quantum mechanics
molecular dynamics
biomolecular modeling
drug development
catalysis
materials modeling
thermodynamics
method development
teaching

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Published Papers (11 papers)

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Research

11 pages, 4215 KiB

Open AccessArticle

Delineating Host–Guest–Solvent Interactions in Solution from Gas-Phase Host–Guest Configurations: Thermodynamic Reversal and Structural Correlation of 24-Crown-8/H⁺/Diaminopropanol Non-Covalent Complexes in Aqueous Solution vs. in the Gas Phase

by Young-Ho Oh, So Yeon Lee, Han Bin Oh and Sungyul Lee

Molecules 2025, 30(8), 1723; https://doi.org/10.3390/molecules30081723 - 11 Apr 2025

Viewed by 158

Abstract

We study the structures of 24-crown-8/H⁺/diaminopropanol (CR/DAPH⁺) and 24-crown-8/CsF/H⁺/diaminopropanol (CR/CsF/DAPH⁺) non-covalent host–guest complexes in both the gas phase and aqueous solution using the density functional theory (DFT) method. We examine the environment (complexation with CR vs. solvation) around the guest functional groups (ammoium, hydroxyl, and amino) in the CR/DAPH⁺ and CR/CsF/DAPH⁺ complexes. We find that the gas-phase configurations with the ‘naked’ hydroxyl/amino devoid of H-bonding with CR or CR/CsF are structurally correlated with the lowest Gibbs free energy conformers in aqueous solution in which the functional groups are solvated off the CR or CR/CsF host. We predict that the latter thermodynamically disadvantageous host–guest configurations would be identified in the gas phase by infrared multiphoton dissociation (IRMPD) spectroscopy, originating from the complexes in aqueous solution. This predicted ‘thermodynamic reversal’ and ‘structural correlation’ of the host–guest configurations in the gas phase vs. in solution are discussed in relation to the possibility of obtaining information on host–guest–solvent interactions in the solution phase from the gas-phase host–guest configurations. Full article

(This article belongs to the Special Issue Computational Chemistry Insights into Molecular Interactions)

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20 pages, 6354 KiB

Open AccessArticle

Binding Free Energy Analysis of Colicin D, E3 and E8 to Their Respective Cognate Immunity Proteins Using Computational Simulations

by Mahesh Koirala and Clifton K. Fagerquist

Molecules 2025, 30(6), 1277; https://doi.org/10.3390/molecules30061277 - 12 Mar 2025

Viewed by 412

Abstract

Colicins are antimicrobial proteins produced by bacteria for the purpose of destroying neighboring bacteria. Colicin activity is neutralized by a specific cognate immunity protein in order to protect the host. This study investigates the structural and binding mechanisms underlying the interaction of colicin-D, -E3 and -E8 to their respective immunity proteins (ImD, Im3 and Im8) using structure prediction, molecular dynamics (MD) simulations and MM-PBSA approach of free energy calculations. High-confidence colicin-immunity (Col-Im) complex structures predicted using AlphaFold2 were subjected to MD simulations of 150 ns with GROMACS and were analyzed for the binding free energy calculation using gmx_MMPBSA. Results showed that the complex of Col_E3-Im3 exhibited the most favorable binding free energy, driven by strong van der Waals and electrostatic interactions. Col_D-ImD and Col_E8-Im8 also showed the favorable binding. Electrostatics and hydrogen bonding emerged as a key factor driving binding and stability, while polar solvation acted as a destabilizing factor across all systems. These outcomes provide an understanding of the molecular mechanisms of Col-Im systems, with potential applications for developing natural antimicrobials for food safety. Full article

(This article belongs to the Special Issue Computational Chemistry Insights into Molecular Interactions)

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13 pages, 1479 KiB

Open AccessArticle

Computation of the pK_a Values of Gallic Acid and Its Anionic Forms in Aqueous Solution: A Self-Similar Transformation Approach for Accurate Proton Hydration Free Energy Estimation

by Marcin Molski

Molecules 2025, 30(3), 742; https://doi.org/10.3390/molecules30030742 - 6 Feb 2025

Cited by 1 | Viewed by 672

Abstract

The Gibbs free energies of gallic acid (GA) and its anionic forms in aqueous solution were computed utilizing density functional theory (DFT) at the LSDA, M062X, B3LYP/QZVP levels, in conjunction with the SMD solvation model. The pK_a values corresponding to the four-step deprotonation of GA were determined through a non-linear self-similar transformation expressed as, pK_a = a⋅pK_a(the)^c which establishes a link between theoretical and experimental pK_a values. This approach replaces the previously employed linear relationship, pK_a = a⋅pK_a(the) + b. The proposed model demonstrates high accuracy in reproducing the experimental pK_a1 = 4.16 ± 0.02, pK_a2 = 8.55 ± 0.01, pK_a3 =11.40 ± 0.10, pK_a4 =12.8 ± 0.40 values of GA, with a standard error (SE) of 0.045 and a mean absolute error (MAE) of 0.019 in pK_a unit. Furthermore, it facilitates the precise determination of the Gibbs free energy of the proton hydration, yielding ∆G(H⁺)_aq = 259.4272(75) [kcal mol⁻¹]. This result conforms acceptably with the experimental value of ∆G(H⁺)_aq = −259.5 [kcal mol⁻¹]. Full article

(This article belongs to the Special Issue Computational Chemistry Insights into Molecular Interactions)

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11 pages, 4035 KiB

Open AccessArticle

Mechanistic Pathways in Cyanide-Mediated Benzoin Condensation: A Comprehensive Electron Localisation Function (ELF) and Catastrophe Theory Analysis of the Umpolung Reaction

by Michal Michalski and Slawomir Berski

Molecules 2025, 30(2), 378; https://doi.org/10.3390/molecules30020378 - 17 Jan 2025

Viewed by 650

Abstract

This research investigates the mechanism of the cyanide-type umpolung reaction in benzoin condensation using topological analysis of ELF and catastrophe theory. The study achieves a comprehensive understanding of the evolution of chemical bonds and non-bonding electron density in the reaction of benzaldehyde and cyanide ions. The results reveal that the reaction proceeds through five transition state structures, with the formation of Lapworth’s cyanohydrin being the rate-determining step. The study characterises topological catastrophes in the evolution of the ELF field and provides a detailed description of the evolution of electron density in the mechanism of the reaction. An in-depth analysis of ELF catastrophes confirms the well-established Lapworth mechanism. Full article

(This article belongs to the Special Issue Computational Chemistry Insights into Molecular Interactions)

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20 pages, 3444 KiB

Open AccessArticle

2,4-Dichlorophenoxyacetic Acid in the Gas and Crystal Phases and Its Intercalation in Montmorillonite—An Experimental and Theoretical Study

by Claro Ignacio Sainz-Díaz, Nelly L. Jorge, Jorge M. Romero, André Grand and Alfonso Hernández-Laguna

Molecules 2025, 30(2), 367; https://doi.org/10.3390/molecules30020367 - 17 Jan 2025

Viewed by 692

Abstract

Many properties of 2,4-dichlorophenoxyacetic acid (2,4-D) depend on its molecular environment, such as whether it is an isolated molecule, a dimer, or in a crystalline state. The molecular geometry, conformational analysis, and vibrational spectrum of 2,4-D were theoretically calculated using Density Functional Theory (DFT) methods. A new slightly more stable conformer was found, which is different to those previously reported. The most stable conformer shows a dimer by means of hydrogen bonds between the carboxylic groups of both molecules, which agrees with the experimental results. The crystal structure of 2,4-D was also calculated with 3D periodical boundary conditions at the DFT level. From the theoretical IR spectra, a vibrational analysis of this molecular species was accomplished, and the bands were reassigned. ¹H and ¹³C NMR in the dissolution and solid states, respectively, showed intramolecular hydrogen bonds between carboxylic acid groups. The dimer is more stable than the isolated molecule. All these results indicated that the dimer can also exist in the solid state, which could explain the low solubility of this compound. In addition, the intercalation of 2,4-D into the confined interlayer space of montmorillonite was also calculated, and it was found that the adsorption is energetically favourable. This result was experimentally confirmed. These findings predicted that these natural clay minerals, which are found in the environment, can be excellent adsorbents for the 2,4-D pollutant. Full article

(This article belongs to the Special Issue Computational Chemistry Insights into Molecular Interactions)

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18 pages, 5518 KiB

Open AccessArticle

Synergistic Effects of Pyrrosia lingua Caffeoylquinic Acid Compounds with Levofloxacin Against Uropathogenic Escherichia coli: Insights from Molecular Dynamics Simulations, Antibiofilm, and Antimicrobial Assessments

by Yan Zhang, Fangfang Jiao, Derong Zeng, Xiang Yu, Yongqiang Zhou, Juan Xue, Wude Yang and Jingjing Guo

Molecules 2024, 29(23), 5679; https://doi.org/10.3390/molecules29235679 - 30 Nov 2024

Viewed by 1082

Abstract

Urinary tract infections (UTIs), primarily caused by uropathogenic Escherichia coli (UPEC), have high morbidity and recurrence rates. Resistance to levofloxacin hydrochloride (LEV), a commonly used treatment for UTIs, is increasingly problematic, exacerbated by biofilm formation mediated by interactions between cyclic di-GMP (c-di-GMP or CDG) and YcgR. In this study, we identified three caffeoylquinic acid compounds from Pyrrosia lingua—chlorogenic acid (CGA), sibiricose A5 (Si-A5), and 3-O-caffeoylquinic acid methyl ester (CAM)—that target YcgR through molecular docking. Biological assays revealed that combining these compounds with levofloxacin hydrochloride significantly enhanced antibacterial activity against standard UPEC strains in a concentration-dependent manner and clinically isolated UPEC strains. Notably, chlorogenic acid and sibiricose A5, when used with levofloxacin hydrochloride, enhanced intracellular c-di-GMP levels and swimming motility, significantly reduced YcgR gene expression, and effectively inhibited biofilm formation of UPEC at multiple time points. Additionally, molecular dynamics simulations elucidated the strong binding of these compounds to YcgR, underscoring the critical roles of residues, such as Arg118 and Asp145. This research serves as a foundation for tackling antibiotic resistance and developing innovative therapeutics for UTIs. Full article

(This article belongs to the Special Issue Computational Chemistry Insights into Molecular Interactions)

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18 pages, 10465 KiB

Open AccessArticle

Quantum Chemical Investigation into the Structural Analysis and Calculated Raman Spectra of Amylose Modeled with Linked Glucose Molecules

by Dapeng Zhang and Naoki Kishimoto

Molecules 2024, 29(12), 2842; https://doi.org/10.3390/molecules29122842 - 14 Jun 2024

Viewed by 1536

Abstract

This study presents a quantum chemical investigation into the structural analysis and calculated Raman spectra of modeled amylose with varying units of linked glucose molecules. We systematically examined the rotation of hydroxymethyl groups and intramolecular hydrogen bonds within these amylose models. Our study found that as the number of linked glucose units increases, the linear structure becomes more complex, resulting in curled, cyclic, or helical structures facilitated by establishing various intramolecular interactions. The hydroxymethyl groups were confirmed to form interactions with oxygen atoms and with hydroxymethyl and hydroxyl groups from adjacent rings in the molecular structures. We identified distinct peaks and selected specific bands applicable in various analytical contexts by comparing their calculated Raman spectra. Representative vibrational modes within selected regions were identified across the different lengths of amylose models, serving as characteristic signatures for linear and more coiled structural conformations. Our findings contribute to a deeper understanding of amylose structures and spectroscopic signatures, with implications for theoretical studies and potential applications. This work provides valuable reference points for the detailed assignment of Raman peaks of amylose structure, facilitating their application in broader research on carbohydrate structures and their associated spectroscopic properties. Full article

(This article belongs to the Special Issue Computational Chemistry Insights into Molecular Interactions)

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18 pages, 1983 KiB

Open AccessArticle

Core-Hole Excitation Spectra of the Oxides and Hydrates of Fullerene C₆₀ and Azafullerene C₅₉N

by Xiong Li, Shuyi Wang, Jingdong Guo, Ziye Wu, Changrui Guo, Shaohong Cai and Mingsen Deng

Molecules 2024, 29(3), 609; https://doi.org/10.3390/molecules29030609 - 26 Jan 2024

Cited by 2 | Viewed by 1412

Abstract

The interaction of fullerenes and their derivatives with environmental molecules such as oxygen or water was crucial for the rational design of low-dimensional materials and devices. In this paper, the near-edge X-ray absorption fine structure (NEXAFS), X-ray emission spectroscopy (XES) and X-ray photoelectron spectroscopy (XPS) shake-up satellites were employed to distinguish the oxides and hydrates of the fullerene C₆₀ and azafullerene C₅₉N families. The study includes various isomers, such as the open [5,6] and closed [6,6] isomers of C₆₀O, C₆₀H(OH), C₆₀-O-C₆₀, C₆₀H-O-C₆₀H, C₅₉N(OH) and C₅₉N-O-C₅₉N, based on density functional theory. These soft X-ray spectra offered comprehensive insights into the molecular orbitals of these azafullerene molecular groups. The oxygen K-edge NEXAFS, carbon and oxygen K-edge XPS shake-up satellite spectra provided valuable tools for distinguishing oxides or hydrates of fullerene C₆₀ and azafullerene C₅₉N. Our findings could significantly benefit the development of fullerene functional molecular materials and expand the application scope of soft X-ray spectroscopy as a molecular fingerprinting tool for the fullerene family. Full article

(This article belongs to the Special Issue Computational Chemistry Insights into Molecular Interactions)

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15 pages, 3236 KiB

Open AccessArticle

Fusing Sequence and Structural Knowledge by Heterogeneous Models to Accurately and Interpretively Predict Drug–Target Affinity

by Xin Zeng, Kai-Yang Zhong, Bei Jiang and Yi Li

Molecules 2023, 28(24), 8005; https://doi.org/10.3390/molecules28248005 - 8 Dec 2023

Cited by 7 | Viewed by 1898

Abstract

Drug–target affinity (DTA) prediction is crucial for understanding molecular interactions and aiding drug discovery and development. While various computational methods have been proposed for DTA prediction, their predictive accuracy remains limited, failing to delve into the structural nuances of interactions. With increasingly accurate and accessible structure prediction of targets, we developed a novel deep learning model, named S2DTA, to accurately predict DTA by fusing sequence features of drug SMILES, targets, and pockets and their corresponding graph structural features using heterogeneous models based on graph and semantic networks. Experimental findings underscored that complex feature representations imparted negligible enhancements to the model’s performance. However, the integration of heterogeneous models demonstrably bolstered predictive accuracy. In comparison to three state-of-the-art methodologies, such as DeepDTA, GraphDTA, and DeepDTAF, S2DTA’s performance became more evident. It exhibited a 25.2% reduction in mean absolute error (MAE) and a 20.1% decrease in root mean square error (RMSE). Additionally, S2DTA showed some improvements in other crucial metrics, including Pearson Correlation Coefficient (PCC), Spearman, Concordance Index (CI), and R², with these metrics experiencing increases of 19.6%, 17.5%, 8.1%, and 49.4%, respectively. Finally, we conducted an interpretability analysis on the effectiveness of S2DTA by bidirectional self-attention mechanism. The analysis results supported that S2DTA was an effective and accurate tool for predicting DTA. Full article

(This article belongs to the Special Issue Computational Chemistry Insights into Molecular Interactions)

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14 pages, 8624 KiB

Open AccessArticle

Computational Modeling Study of the Binding of Aging and Non-Aging Inhibitors with Neuropathy Target Esterase

by Wenxiong Wu and Pan Wang

Molecules 2023, 28(23), 7747; https://doi.org/10.3390/molecules28237747 - 24 Nov 2023

Viewed by 1143

Abstract

Neuropathy target esterase (NTE) is a serine hydrolase with phospholipase B activity, which is involved in maintaining the homeostasis of phospholipids. It can be inhibited by aging inhibitors such as some organophosphorus (OP) compounds, which leads to delayed neurotoxicity with distal degeneration of axons. However, the detailed binding conformation of aging and non-aging inhibitors with NTE is not known. In this study, new computational models were constructed by using MODELLER 10.3 and AlphaFold2 to further investigate the inhibition mechanism of aging and non-aging compounds using molecular docking. The results show that the non-aging compounds bind the hydrophobic pocket much deeper than aging compounds and form the hydrophobic interaction with Phe1066. Therefore, the unique binding conformation of non-aging compounds may prevent the aging reaction. These important differences of the binding conformations of aging and non-aging inhibitors with NTE may help explain their different inhibition mechanism and the protection of non-aging NTE inhibitors against delayed neuropathy. Full article

(This article belongs to the Special Issue Computational Chemistry Insights into Molecular Interactions)

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18 pages, 9037 KiB

Open AccessArticle

A Holistic View of the Interactions between Electron-Deficient Systems: Clustering of Beryllium and Magnesium Hydrides and Halides

by Otilia Mó, M. Merced Montero-Campillo, Manuel Yáñez, Ibon Alkorta and José Elguero

Molecules 2023, 28(22), 7507; https://doi.org/10.3390/molecules28227507 - 9 Nov 2023

Cited by 2 | Viewed by 1406

Abstract

In the search for common bonding patterns in pure and mixed clusters of beryllium and magnesium derivatives, the most stable dimers and trimers involving BeX₂ and MgX₂ (X = H, F, Cl) have been studied in the gas phase using B3LYP and M06-2X DFT methods and the G4 ab initio composite procedure. To obtain some insight into their structure, stability, and bonding characteristics, we have used two different energy decomposition formalisms, namely MBIE and LMO-EDA, in parallel with the analysis of the electron density with the help of QTAIM, ELF, NCIPLOT, and AdNDP approaches. Some interesting differences are already observed in the dimers, where the stability sequence observed for the hydrides differs entirely from that of the fluorides and chlorides. Trimers also show some peculiarities associated with the presence of compact trigonal cyclic structures that compete in stability with the more conventional hexagonal and linear forms. As observed for dimers, the stability of the trimers changes significantly from hydrides to fluorides or chlorides. Although some of these clusters were previously explored in the literature, the novelty of this work is to provide a holistic approach to the entire series of compounds by using chemical bonding tools, allowing us to understand the stability trends in detail and providing insights for a significant number of new, unexplored structures. Full article

(This article belongs to the Special Issue Computational Chemistry Insights into Molecular Interactions)

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