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Structure, Energy, and Dynamics of Molecular Interactions

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Informatics".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 37501

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Special Issue Editors

Dr. Csaba Hetényi

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Guest Editor

Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti út 12, 7624 Pécs, Hungary
Interests: proteins; molecular structure; thermodynamics; drug design; chemoinformatics
Special Issues, Collections and Topics in MDPI journals

Dr. Uko Maran

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Guest Editor

Institute of Chemistry, University of Tartu, 14A Ravila Str., 50411 Tartu, Estonia
Interests: theoretical and computer chemistry; malaria drug development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The organization of matter is based on intra- and intermolecular interactions. Understanding the structure and thermodynamics of molecular interactions is therefore key to answering to the challenges of drug design and the development of new materials with unusual properties. Whereas molecular interactions occur in such distant challenges of living nature and lifeless industrial plants, the same physicochemical laws apply to both situations. The present Special Issue aims to demonstrate the diversity of research focusing on the solution of important issues in understanding molecular interactions via experimental measurements and/or theoretical calculations. Contributions are welcome from all fields of method development, theory, and applications. The Special Issue covers both living nature and inorganic materials. Studies connecting the dynamics of molecular interactions to natural phenomena are of particular interest.

Dr. Csaba Hetényi
Dr. Uko Maran
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Binding
Conformation
Affinity
Complex
Energy
Structure
Isothermal titration calorimetry
Crystallography
Molecular mechanics
Quantum chemistry
Quantitative structure–activity relationship
Reaction kinetics
Inhibitor
Substrate
Target
Ligand
Receptor
Surface
Interface

Published Papers (14 papers)

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Research

Jump to: Review

28 pages, 7725 KiB

Open AccessArticle

Machine Learning Quantitative Structure–Property Relationships as a Function of Ionic Liquid Cations for the Gas-Ionic Liquid Partition Coefficient of Hydrocarbons

by Karl Marti Toots, Sulev Sild, Jaan Leis, William E. Acree, Jr. and Uko Maran

Int. J. Mol. Sci. 2022, 23(14), 7534; https://doi.org/10.3390/ijms23147534 - 7 Jul 2022

Cited by 5 | Viewed by 1542

Abstract

Ionic liquids (ILs) are known for their unique characteristics as solvents and electrolytes. Therefore, new ILs are being developed and adapted as innovative chemical environments for different applications in which their properties need to be understood on a molecular level. Computational data-driven methods provide means for understanding of properties at molecular level, and quantitative structure–property relationships (QSPRs) provide the framework for this. This framework is commonly used to study the properties of molecules in ILs as an environment. The opposite situation where the property is considered as a function of the ionic liquid does not exist. The aim of the present study was to supplement this perspective with new knowledge and to develop QSPRs that would allow the understanding of molecular interactions in ionic liquids based on the structure of the cationic moiety. A wide range of applications in electrochemistry, separation and extraction chemistry depends on the partitioning of solutes between the ionic liquid and the surrounding environment that is characterized by the gas-ionic liquid partition coefficient. To model this property as a function of the structure of a cationic counterpart, a series of ionic liquids was selected with a common bis-(trifluoromethylsulfonyl)-imide anion, [Tf2N]⁻, for benzene, hexane and cyclohexane. MLR, SVR and GPR machine learning approaches were used to derive data-driven models and their performance was compared. The cross-validation coefficients of determination in the range 0.71–0.93 along with other performance statistics indicated a strong accuracy of models for all data series and machine learning methods. The analysis and interpretation of descriptors revealed that generally higher lipophilicity and dispersion interaction capability, and lower polarity in the cations induces a higher partition coefficient for benzene, hexane, cyclohexane and hydrocarbons in general. The applicability domain analysis of models concluded that there were no highly influential outliers and the models are applicable to a wide selection of cation families with variable size, polarity and aliphatic or aromatic nature. Full article

(This article belongs to the Special Issue Structure, Energy, and Dynamics of Molecular Interactions)

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24 pages, 69900 KiB

Open AccessArticle

Structure–Function Relationships in the Human P-Glycoprotein (ABCB1): Insights from Molecular Dynamics Simulations

by Liadys Mora Lagares, Yunierkis Pérez-Castillo, Nikola Minovski and Marjana Novič

Int. J. Mol. Sci. 2022, 23(1), 362; https://doi.org/10.3390/ijms23010362 - 29 Dec 2021

Cited by 25 | Viewed by 2835

Abstract

P-Glycoprotein (P-gp) is a transmembrane protein belonging to the ATP binding cassette superfamily of transporters, and it is a xenobiotic efflux pump that limits intracellular drug accumulation by pumping compounds out of cells. P-gp contributes to a reduction in toxicity, and has broad substrate specificity. It is involved in the failure of many cancer and antiviral chemotherapies due to the phenomenon of multidrug resistance (MDR), in which the membrane transporter removes chemotherapeutic drugs from target cells. Understanding the details of the ligand–P-gp interaction is therefore critical for the development of drugs that can overcome the MDR phenomenon, for the early identification of P-gp substrates that will help us to obtain a more effective prediction of toxicity, and for the subsequent outdesign of substrate properties if needed. In this work, a series of molecular dynamics (MD) simulations of human P-gp (hP-gp) in an explicit membrane-and-water environment were performed to investigate the effects of binding different compounds on the conformational dynamics of P-gp. The results revealed significant differences in the behaviour of P-gp in the presence of active and non-active compounds within the binding pocket, as different patterns of movement were identified that could be correlated with conformational changes leading to the activation of the translocation mechanism. The predicted ligand–P-gp interactions are in good agreement with the available experimental data, as well as the estimation of the binding-free energies of the studied complexes, demonstrating the validity of the results derived from the MD simulations. Full article

(This article belongs to the Special Issue Structure, Energy, and Dynamics of Molecular Interactions)

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17 pages, 3992 KiB

Open AccessArticle

Aggregation Properties of Albumin in Interacting with Magnetic Fluids

by Elena N. Velichko, Elina K. Nepomnyashchaya, Maksim A. Baranov, Alexey N. Skvortsov, Ivan V. Pleshakov and Ge Dong

Int. J. Mol. Sci. 2021, 22(19), 10734; https://doi.org/10.3390/ijms221910734 - 3 Oct 2021

Cited by 5 | Viewed by 1916

Abstract

In this study, interactions of Fe₃O₄ magnetic nanoparticles with serum albumin biomolecules in aqueous solutions were considered. The studies were conducted with the laser correlation spectroscopy and optical analysis of dehydrated films. It was shown that the addition of magnetite to an albumin solution at low concentrations of up to 10⁻⁶ g/L led to the formation of aggregates with sizes of up to 300 nm in the liquid phase and an increase in the number of spiral structures in the dehydrated films, which indicated an increase in their stability. With a further increase in the magnetite concentration in the solution (from 10⁻⁴ g/L), the magnetic particles stuck together and to albumin, thus forming aggregates with sizes larger than 1000 nm. At the same time, the formation of morphological structures in molecular films was disturbed, and a characteristic decrease in their stability occurred. Most stable films were formed at low concentrations of magnetic nanoparticles (less than 10⁻⁴ g/L) when small albumin–magnetic nanoparticle aggregates were formed. These results are important for characterizing the interaction processes of biomolecules with magnetic nanoparticles and can be useful for predicting the stability of biomolecular films with the inclusion of magnetite particles. Full article

(This article belongs to the Special Issue Structure, Energy, and Dynamics of Molecular Interactions)

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13 pages, 7656 KiB

Open AccessArticle

Chelerythrine Chloride: A Potential Rumen Microbial Urease Inhibitor Screened by Targeting UreG

by Xiaoyin Zhang, Yue He, Zhanbo Xiong, Min Li, Ming Li, Nan Zheng, Shengguo Zhao and Jiaqi Wang

Int. J. Mol. Sci. 2021, 22(15), 8212; https://doi.org/10.3390/ijms22158212 - 30 Jul 2021

Cited by 10 | Viewed by 1959

Abstract

Inhibition of ruminal microbial urease is of particular interest due to its crucial role in regulating urea-N utilization efficiency and nitrogen pollution in the livestock industry. Acetohydroxamic acid (AHA) is currently the only commercially available urease inhibitor, but it has adverse side effects. The urease accessory protein UreG, which facilitates the functional incorporation of the urease nickel metallocentre, has been proposed in developing urease inhibitor through disrupting urease maturation. The objective of this study was to screen natural compounds as potential urease inhibitors by targeting UreG in a predominant ruminal microbial urease. In silico screening and in vitro tests for potential inhibitors were performed using molecular docking and an assay for the GTPase activity of UreG. Chelerythrine chloride was selected as a potential urease inhibitor of UreG with an inhibition concentration IC₅₀ value of 18.13 μM. It exhibited mixed inhibition, with the K_i value being 26.28 μM. We further explored its inhibition mechanism using isothermal titration calorimetry (ITC) and circular dichroism (CD) spectroscopy, and we found that chelerythrine chloride inhibited the binding of nickel to UreG and induced changes in the secondary structure, especially the α-helix and β-sheet of UreG. Chelerythrine chloride formed a pi-anion interaction with the Asp41 residue of UreG, which is an important residue in initiating the conformational changes of UreG. In conclusion, chelerythrine chloride exhibited a potential inhibitory effect on urease, which provided new evidence for strategies to develop novel urease inhibitors targeting UreG to reduce nitrogen excretion from ruminants. Full article

(This article belongs to the Special Issue Structure, Energy, and Dynamics of Molecular Interactions)

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19 pages, 2420 KiB

Open AccessArticle

Characterization of the Intramolecular Interactions and Regulatory Mechanisms of the Scaffold Protein Tks4

by Balázs Merő, Kitti Koprivanacz, Anna Cserkaszky, László Radnai, Virag Vas, Gyöngyi Kudlik, Gergő Gógl, Péter Sok, Ádám L. Póti, Bálint Szeder, László Nyitray, Attila Reményi, Miklós Geiszt and László Buday

Int. J. Mol. Sci. 2021, 22(15), 8103; https://doi.org/10.3390/ijms22158103 - 28 Jul 2021

Cited by 2 | Viewed by 2314

Abstract

The scaffold protein Tks4 is a member of the p47^phox-related organizer superfamily. It plays a key role in cell motility by being essential for the formation of podosomes and invadopodia. In addition, Tks4 is involved in the epidermal growth factor (EGF) signaling pathway, in which EGF induces the translocation of Tks4 from the cytoplasm to the plasma membrane. The evolutionarily-related protein p47^phox and Tks4 share many similarities in their N-terminal region: a phosphoinositide-binding PX domain is followed by two SH3 domains (so called “tandem SH3”) and a proline-rich region (PRR). In p47^phox, the PRR is followed by a relatively short, disordered C-terminal tail region containing multiple phosphorylation sites. These play a key role in the regulation of the protein. In Tks4, the PRR is followed by a third and a fourth SH3 domain connected by a long (~420 residues) unstructured region. In p47^phox, the tandem SH3 domain binds the PRR while the first SH3 domain interacts with the PX domain, thereby preventing its binding to the membrane. Based on the conserved structural features of p47^phox and Tks4 and the fact that an intramolecular interaction between the third SH3 and the PX domains of Tks4 has already been reported, we hypothesized that Tks4 is similarly regulated by autoinhibition. In this study, we showed, via fluorescence-based titrations, MST, ITC, and SAXS measurements, that the tandem SH3 domain of Tks4 binds the PRR and that the PX domain interacts with the third SH3 domain. We also investigated a phosphomimicking Thr-to-Glu point mutation in the PRR as a possible regulator of intramolecular interactions. Phosphatidylinositol-3-phosphate (PtdIns(3)P) was identified as the main binding partner of the PX domain via lipid-binding assays. In truncated Tks4 fragments, the presence of the tandem SH3, together with the PRR, reduced PtdIns(3)P binding, while the presence of the third SH3 domain led to complete inhibition. Full article

(This article belongs to the Special Issue Structure, Energy, and Dynamics of Molecular Interactions)

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20 pages, 3391 KiB

Open AccessArticle

Thermodynamics and Intermolecular Interactions of Nicotinamide in Neat and Binary Solutions: Experimental Measurements and COSMO-RS Concentration Dependent Reactions Investigations

by Piotr Cysewski, Maciej Przybyłek, Anna Kowalska and Natalia Tymorek

Int. J. Mol. Sci. 2021, 22(14), 7365; https://doi.org/10.3390/ijms22147365 - 8 Jul 2021

Cited by 16 | Viewed by 3167

Abstract

In this study, the temperature-dependent solubility of nicotinamide (niacin) was measured in six neat solvents and five aqueous-organic binary mixtures (methanol, 1,4-dioxane, acetonitrile, DMSO and DMF). It was discovered that the selected set of organic solvents offer all sorts of solvent effects, including co-solvent, synergistic, and anti-solvent features, enabling flexible tuning of niacin solubility. In addition, differential scanning calorimetry was used to characterize the fusion thermodynamics of nicotinamide. In particular, the heat capacity change upon melting was measured. The experimental data were interpreted by means of COSMO-RS-DARE (conductor-like screening model for realistic solvation–dimerization, aggregation, and reaction extension) for concentration dependent reactions. The solute–solute and solute–solvent intermolecular interactions were found to be significant in all of the studied systems, which was proven by the computed mutual affinity of the components at the saturated conditions. The values of the Gibbs free energies of pair formation were derived at an advanced level of theory (MP2), including corrections for electron correlation and zero point vibrational energy (ZPE). In all of the studied systems the self-association of nicotinamide was found to be a predominant intermolecular complex, irrespective of the temperature and composition of the binary system. The application of the COSMO-RS-DARE approach led to a perfect match between the computed and measured solubility data, by optimizing the parameter of intermolecular interactions. Full article

(This article belongs to the Special Issue Structure, Energy, and Dynamics of Molecular Interactions)

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20 pages, 2834 KiB

Open AccessArticle

Solvent Screening for Solubility Enhancement of Theophylline in Neat, Binary and Ternary NADES Solvents: New Measurements and Ensemble Machine Learning

by Piotr Cysewski, Tomasz Jeliński, Patryk Cymerman and Maciej Przybyłek

Int. J. Mol. Sci. 2021, 22(14), 7347; https://doi.org/10.3390/ijms22147347 - 8 Jul 2021

Cited by 19 | Viewed by 3748

Abstract

Theophylline, a typical representative of active pharmaceutical ingredients, was selected to study the characteristics of experimental and theoretical solubility measured at 25 °C in a broad range of solvents, including neat, binary mixtures and ternary natural deep eutectics (NADES) prepared with choline chloride, polyols and water. There was a strong synergistic effect of organic solvents mixed with water, and among the experimentally studied binary systems, the one containing DMSO with water in unimolar proportions was found to be the most effective in theophylline dissolution. Likewise, for NADES, the addition of water (0.2 molar fraction) resulted in increased solubility compared to pure eutectics, with the highest solubilisation potential offered by the composition of choline chloride with glycerol. The ensemble of Statistica Automated Neural Networks (SANNs) developed using intermolecular interactions in pure systems has been found to be a very accurate model for solubility computations. This machine learning protocol was also applied as an extensive screening for potential solvents with higher solubility of theophylline. Such solvents were identified in all three subgroups, including neat solvents, binary mixtures and ternary NADES systems. Some methodological considerations of SANNs applications for future modelling were also provided. Although the developed protocol is focused exclusively on theophylline solubility, it also has general importance and can be used for the development of predictive models adequate for solvent screening of other compounds in a variety of systems. Formulation of such a model offers rational guidance for the selection of proper candidates as solubilisers in the designed solvents screening. Full article

(This article belongs to the Special Issue Structure, Energy, and Dynamics of Molecular Interactions)

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17 pages, 3680 KiB

Open AccessArticle

Evidence of the CH···O HydrogenBonding in Imidazolium-Based Ionic Liquids from Far-Infrared Spectroscopy Measurements and DFT Calculations

by Oriele Palumbo, Adriano Cimini, Francesco Trequattrini, Jean-Blaise Brubach, Pascale Roy and Annalisa Paolone

Int. J. Mol. Sci. 2021, 22(11), 6155; https://doi.org/10.3390/ijms22116155 - 7 Jun 2021

Cited by 11 | Viewed by 2599

Abstract

Knowledge of all the intermolecular forces occurring in ionic liquids (ILs) is essential to master their properties. Aiming at investigating the weaker hydrogen bonding in aprotic liquids, the present work combined computational study and far-infrared spectroscopy on four imidazolium-based ILs with different anions. The DFT calculations of the ionic couples, using the ωB97X-D functional and considering both the empirical dispersion corrections and the presence of a polar solvent, show that, for all samples, the lowest energy configurations of the ion pair present H atoms, directly bound to C atoms of the cation and close to O atoms of the anion, capable of creating moderate to weak hydrogen bonding with anions. For the liquids containing anions of higher bonding ability, the absorption curves generated from the calculated vibrational frequencies and intensities show absorption bands between 100 and 125 cm⁻¹ corresponding to the stretching of the hydrogen bond. These indications are in complete agreement with the presently reported temperature dependence of the far-infrared spectrum, where the stretching modes of the hydrogen bonding are detected only for samples presenting a moderate interaction and become particularly prominent at low temperatures. Moreover, from the analysis of the infrared spectra, the occurrence of various phase transitions as a function of temperature was detected, and the difference in the average energy between the H-bonded and the dispersion-governed molecular configurations was evaluated. Full article

(This article belongs to the Special Issue Structure, Energy, and Dynamics of Molecular Interactions)

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18 pages, 5848 KiB

Open AccessArticle

Ensemble-Based Analysis of the Dynamic Allostery in the PSD-95 PDZ3 Domain in Relation to the General Variability of PDZ Structures

by Dániel Dudola, Anett Hinsenkamp and Zoltán Gáspári

Int. J. Mol. Sci. 2020, 21(21), 8348; https://doi.org/10.3390/ijms21218348 - 6 Nov 2020

Cited by 4 | Viewed by 2394

Abstract

PDZ domains are abundant interaction hubs found in a number of different proteins and they exhibit characteristic differences in their structure and ligand specificity. Their internal dynamics have been proposed to contribute to their biological activity via changes in conformational entropy upon ligand binding and allosteric modulation. Here we investigate dynamic structural ensembles of PDZ3 of the postsynaptic protein PSD-95, calculated based on previously published backbone and side-chain S

^{2}

order parameters. We show that there are distinct but interdependent structural rearrangements in PDZ3 upon ligand binding and the presence of the intramolecular allosteric modulator helix

α

3. We have also compared these rearrangements in PDZ1-2 of PSD-95 and the conformational diversity of an extended set of PDZ domains available in the PDB database. We conclude that although the opening-closing rearrangement, occurring upon ligand binding, is likely a general feature for all PDZ domains, the conformer redistribution upon ligand binding along this mode is domain-dependent. Our findings suggest that the structural and functional diversity of PDZ domains is accompanied by a diversity of internal motional modes and their interdependence. Full article

(This article belongs to the Special Issue Structure, Energy, and Dynamics of Molecular Interactions)

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12 pages, 2976 KiB

Open AccessArticle

Enaminone Substituted Resorcin[4]arene—Sealing of an Upper-Rim with a Directional System of Hydrogen-Bonds

by Anna Szafraniec, Marcin Grajda, Hanna Jędrzejewska, Agnieszka Szumna and Waldemar Iwanek

Int. J. Mol. Sci. 2020, 21(20), 7494; https://doi.org/10.3390/ijms21207494 - 11 Oct 2020

Cited by 3 | Viewed by 2035

Abstract

The paper presents the synthesis of an enaminone resorcin[4]arene via a thermally activated o-quinomethide. The crystal structure indicates that in the solid state all enaminone units participate in a unidirectional seam of 12 intramolecular hydrogen bonds that are formed around the cavity. The molecule exhibits C₂ symmetry, with two opposite-laying enaminone units directed inside the cavity (“in”), and the other two units outside the cavity (“out”). In the solution the enaminone resorcin[4]arene exists as a mixture of conformers with distribution controlled by temperature and solvent. The experimental data are compared with the results of theoretical calculations using DFT B3LYP/6-31G(d,p) and fast semi-empirical DFTB/GFN2-xTB method in various solvents. Full article

(This article belongs to the Special Issue Structure, Energy, and Dynamics of Molecular Interactions)

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14 pages, 4871 KiB

Open AccessArticle

Intramolecular Hydrogen Bond Driven Conformational Selectivity of Coumarin Derivatives of Resorcin[4]arene

by Anna Szafraniec and Waldemar Iwanek

Int. J. Mol. Sci. 2020, 21(17), 6160; https://doi.org/10.3390/ijms21176160 - 26 Aug 2020

Cited by 4 | Viewed by 2364

Abstract

In this study, the synthesis and structure of 4-aminocoumarin derivatives of resorcin[4]arene were investigated. Spectroscopic analysis and quantum mechanical calculations showed that this molecule undertakes a crown-in conformation in chloroform. The conformations of the aminocoumarin derivative of resorcin[4]arene were compared with a hydroxycoumarin derivative of resorcin[4]arene, and the effect of the substituent on the conformational selectivity of the coumarin derivatives of resorcin[4]arene was demonstrated. Both UV-VIS and fluorescence spectroscopy for the coumarin derivative of resorcin[4]arene (3) were performed, and a strong fluorescence quenching of derivative 3 compared to 4-aminocoumarin was observed. Full article

(This article belongs to the Special Issue Structure, Energy, and Dynamics of Molecular Interactions)

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18 pages, 5098 KiB

Open AccessArticle

Tuning of Molecular Electrostatic Potential Enables Efficient Charge Transport in Crystalline Azaacenes: A Computational Study

by Andrey Sosorev, Dmitry Dominskiy, Ivan Chernyshov and Roman Efremov

Int. J. Mol. Sci. 2020, 21(16), 5654; https://doi.org/10.3390/ijms21165654 - 6 Aug 2020

Cited by 9 | Viewed by 2786

Abstract

The chemical versatility of organic semiconductors provides nearly unlimited opportunities for tuning their electronic properties. However, despite decades of research, the relationship between molecular structure, molecular packing and charge mobility in these materials remains poorly understood. This reduces the search for high-mobility organic semiconductors to the inefficient trial-and-error approach. For clarifying the abovementioned relationship, investigations of the effect of small changes in the chemical structure on organic semiconductor properties are particularly important. In this study, we computationally address the impact of the substitution of C-H atom pairs by nitrogen atoms (N-substitution) on the molecular properties, molecular packing and charge mobility of crystalline oligoacenes. We observe that besides decreasing frontier molecular orbital levels, N-substitution dramatically alters molecular electrostatic potential, yielding pronounced electron-rich and electron-deficient areas. These changes in the molecular electrostatic potential strengthen face-to-face and edge-to-edge interactions in the corresponding crystals and result in the crossover from the herringbone packing motif to π-stacking. When the electron-rich and electron-deficient areas are large, sharply defined and, probably, have a certain symmetry, calculated charge mobility increases up to 3–4 cm²V⁻¹s⁻¹. The results obtained highlight the potential of azaacenes for application in organic electronic devices and are expected to facilitate the rational design of organic semiconductors for the steady improvement of organic electronics. Full article

(This article belongs to the Special Issue Structure, Energy, and Dynamics of Molecular Interactions)

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18 pages, 2189 KiB

Open AccessArticle

A Systematic Test of Receptor Binding Kinetics for Ligands in Tumor Necrosis Factor Superfamily by Computational Simulations

by Zhaoqian Su and Yinghao Wu

Int. J. Mol. Sci. 2020, 21(5), 1778; https://doi.org/10.3390/ijms21051778 - 5 Mar 2020

Cited by 7 | Viewed by 3533

Abstract

Ligands in the tumor necrosis factor (TNF) superfamily are one major class of cytokines that bind to their corresponding receptors in the tumor necrosis factor receptor (TNFR) superfamily and initiate multiple intracellular signaling pathways during inflammation, tissue homeostasis, and cell differentiation. Mutations in the genes that encode TNF ligands or TNFR receptors result in a large variety of diseases. The development of therapeutic treatment for these diseases can be greatly benefitted from the knowledge on binding properties of these ligand–receptor interactions. In order to complement the limitations in the current experimental methods that measure the binding constants of TNF/TNFR interactions, we developed a new simulation strategy to computationally estimate the association and dissociation between a ligand and its receptor. We systematically tested this strategy to a comprehensive dataset that contained structures of diverse complexes between TNF ligands and their corresponding receptors in the TNFR superfamily. We demonstrated that the binding stabilities inferred from our simulation results were compatible with existing experimental data. We further compared the binding kinetics of different TNF/TNFR systems, and explored their potential functional implication. We suggest that the transient binding between ligands and cell surface receptors leads into a dynamic nature of cross-membrane signal transduction, whereas the slow but strong binding of these ligands to the soluble decoy receptors is naturally designed to fulfill their functions as inhibitors of signal activation. Therefore, our computational approach serves as a useful addition to current experimental techniques for the quantitatively comparison of interactions across different members in the TNF and TNFR superfamily. It also provides a mechanistic understanding to the functions of TNF-associated cell signaling pathways. Full article

(This article belongs to the Special Issue Structure, Energy, and Dynamics of Molecular Interactions)

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Review

Jump to: Research

13 pages, 13274 KiB

Open AccessReview

The Two-Step Clustering Approach for Metastable States Learning

by Hangjin Jiang and Xiaodan Fan

Int. J. Mol. Sci. 2021, 22(12), 6576; https://doi.org/10.3390/ijms22126576 - 19 Jun 2021

Cited by 1 | Viewed by 2776

Abstract

Understanding the energy landscape and the conformational dynamics is crucial for studying many biological or chemical processes, such as protein–protein interaction and RNA folding. Molecular Dynamics (MD) simulations have been a major source of dynamic structure. Although many methods were proposed for learning metastable states from MD data, some key problems are still in need of further investigation. Here, we give a brief review on recent progresses in this field, with an emphasis on some popular methods belonging to a two-step clustering framework, and hope to draw more researchers to contribute to this area. Full article

(This article belongs to the Special Issue Structure, Energy, and Dynamics of Molecular Interactions)

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