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

Deadline for manuscript submissions: closed (20 March 2025) | Viewed by 7242

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Dr. Maria Alexandra Mernea

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Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Bucharest, Romania
Interests: molecular modeling; molecular dynamics simulations; modeling of biomolecules and their interactions
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Dan Mihailescu

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Dear Colleagues,

Recent advances in computational power, algorithmic efficiency, and interdisciplinary collaborations have led to significant breakthroughs in molecular modeling. The goal of this Special Issue is to highlight the state-of-the-art research in molecular modeling and its applications in a variety of fields, including new material development and pharmaceuticals. The contributions in this Special Issue highlight the critical role that molecular modeling plays in deepening our understanding of complex molecular systems by examining fresh approaches, theoretical discoveries, and practical applications of this field. This Special Issue offers an overview of current trends, difficulties, and future directions in molecular modeling, offering insightful viewpoints for researchers, practitioners, and educators alike.

Dr. Maria Alexandra Mernea
Prof. Dr. Dan Mihailescu
Guest Editors

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Keywords

molecular modeling
computational chemistry
drug design
material science
biomolecular interactions
algorithmic advances
theoretical chemistry
simulation techniques
predictive modeling
interdisciplinary applications

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Published Papers (10 papers)

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Research

15 pages, 5424 KiB

Open AccessArticle

Shortened PGLYRP1 Peptides Regulate Antitumor Activity of Cytotoxic Lymphocytes via TREM-1 Receptor: From Biology to Bioinformatics

by Daria M. Yurkina, Kirill A. Shcherbakov, Elena A. Romanova, Anna V. Tvorogova, Alexey M. Feoktistov, Georgii P. Georgiev, Denis V. Yashin and Lidia P. Sashchenko

Int. J. Mol. Sci. 2025, 26(9), 4069; https://doi.org/10.3390/ijms26094069 - 25 Apr 2025

Abstract

The pro-inflammatory immune response plays an important role in protecting the body from pathogens and tumors. In this study, we were able to identify three peptides of the innate immunity protein PGLYRP1 (Tag7) that could regulate the activity of the TREM-1 receptor. TREM-1 receptor activation on monocytes triggers the appearance of antitumor lymphocytes. All three peptides studied (17.0, N9, and N15) bind with the TREM-1 receptor with the Kds 1.32 ± 0.2 nM, 9.66 ± 0.5 nM, and 7.43 ± 0.4 nM, respectively. An N9 peptide inhibiting the activity of the receptor was identified in addition to two peptides (N9 and N15) that jointly trigger the activation of the receptor. The conducted molecular docking study revealed amino acid residues (Ile57, Ile58, Glu106, Ser108, Leu110, Tyr116, Pro118, Pro119, Arg130, and Val 132), necessary for various functions of peptides, providing important knowledge for understanding the mechanism of activation of this receptor that can also serve as a basis for the development of therapeutic drugs to regulate its activity in the treatment of autoimmune diseases and tumors. Full article

(This article belongs to the Special Issue Molecular Modeling: Latest Advances and Applications)

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22 pages, 13568 KiB

Open AccessArticle

Molecular Basis of High-Blood-Pressure-Enhanced and High-Fever-Temperature-Weakened Receptor-Binding Domain/Peptidase Domain Binding: A Molecular Dynamics Simulation Study

by Xubin Xie, Yu Zhang, Ying Fang, Jianhua Wu and Quhuan Li

Int. J. Mol. Sci. 2025, 26(7), 3250; https://doi.org/10.3390/ijms26073250 - 31 Mar 2025

Viewed by 249

Abstract

The entry and infection of the Severe Acute Respiratory Syndrome Coronavirus 2 virus (SARS-CoV-2) involve recognition and binding of the receptor-binding domain (RBD) of the virus surface spike protein to the peptidase domain (PD) of the host cellular Angiotensin-Converting Enzyme-2 (ACE2) receptor. ACE2 is also involved in normal blood pressure control. An association between hypertension and COVID-19 severity and fatality is evident, but how hypertension predisposes patients diagnosed with COVID-19 to unfavorable outcomes remains unclear. High temperature early during SARS-CoV-2 infection impairs binding to human cells and retards viral progression. Low body temperature can prelude poor prognosis. In this study, all-atom molecular dynamics simulations were performed to examine the effects of high pressure and temperature on RBD/PD binding. A high blood pressure of 940 mmHg enhanced RBD/PD binding. A high temperature above 315 K significantly weakened RBD/PD binding, while a low temperature of 305 K enhanced binding. The curvature of the PD α1-helix and proximity of the PD β3β4-hairpin tip to the RBM motif affected the compactness of the binding interface and, hence, binding affinity. These findings provide novel insights into the underlying mechanisms by which hypertension predisposes patients to unfavorable outcomes in COVID-19 and how an initial high temperature retards viral progression. Full article

(This article belongs to the Special Issue Molecular Modeling: Latest Advances and Applications)

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11 pages, 1088 KiB

Open AccessCommunication

Inhibitory Potential of Boscalid and Abamectin Towards Acetylcholinesterase and Butyrylcholinesterase: Computational and In Vitro Studies

by Biljana Arsić, Stefan Petrović, Budimir S. Ilić, Milka Vrecl, Tomaž Trobec, Kristina Sepčić, Robert Frangež, Sanja M. Glišić and Jelena S. Milićević

Int. J. Mol. Sci. 2025, 26(7), 2865; https://doi.org/10.3390/ijms26072865 - 21 Mar 2025

Viewed by 364

Abstract

The growing demand for agricultural products has led to the misuse of pesticides, resulting in the use of higher concentrations of these substances. This has led to an increase in toxicity imposed on other beneficial organisms and to the bioaccumulation of toxic pesticide concentrations in the bodies of both pests and non-target organisms, as well as in their end users, including humans. In this study, the neurotoxic potential of the commonly used pesticides abamectin (an insecticide) and boscalid (a fungicide) was evaluated. Both in vitro and in silico studies showed that human butyrylcholinesterase is not a target for abamectins B1A and B1B. Boscalid showed a modest Glide score (−28.8 kJ/mol) and a considerably higher IC₅₀ (308.8 µM) against human butyrylcholinesterase than the approved inhibitor (2-((1-(benzenesulfonyl)-1H-indol-4-yl)oxy)ethyl)(benzyl)amine (IC₅₀ = 0.473 µM). However, due to its non-mutagenicity and low toxicity, structural analogues of boscalid might be considered as candidates for the symptomatic treatment of Alzheimer’s disease. Molecular dynamics simulations over 100 ns confirmed the stability of boscalid within the active site of butyrylcholinesterase, where it maintained key interactions with catalytic residues such as Trp82 and His438. These findings highlight its potential as a starting point for structure-based drug design strategies aimed at optimizing cholinesterase inhibitors with improved pharmacokinetic properties. According to absorption, distribution, metabolism, elimination, and toxicity studies, boscalid is orally active, which cannot be attributed to abamectins B1A and B1B. Full article

(This article belongs to the Special Issue Molecular Modeling: Latest Advances and Applications)

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16 pages, 4014 KiB

Open AccessArticle

Comprehensive Transcriptomic Analyses of Silk-Associated Genes and Functional Characterization of Key Silk Fibroins in Plutella xylostella

by Rui-Chang Niu, Fan-Xin Meng, Qing-Hui Zeng, Yi-Jing Wang, Tong-Xian Liu, Dong Chu and Shi-Ze Zhang

Int. J. Mol. Sci. 2025, 26(7), 2842; https://doi.org/10.3390/ijms26072842 - 21 Mar 2025

Cited by 1 | Viewed by 290

Abstract

The diamondback moth (DBM), Plutella xylostella (Lepidoptera: Plutellidae), is a serious agricultural pest that utilizes silk as a defensive mechanism, with silk fibroins playing a pivotal role in this process. Through comprehensive transcriptomic analyses, we identified 3452 differentially expressed genes (DEGs) co-expressed in the silk gland of P. xylostella and associated with silk production. The Gene Ontology (GO) analysis revealed enrichment in categories related to protein synthesis, secretion, and extracellular matrix organization, while Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis linked these genes to amino acid metabolism and protein processing pathways. Additionally, we identified three key silk fibroin genes: silk fibroin heavy chain (FibH), silk fibroin light chain (FibL), and fibrohexamerin (P25). We characterized the structure of these genes and analyzed the phylogenetic relationships, amino acid composition, hydrophilicity, and other physicochemical properties of the encoded silk fibroin proteins. The expression profiles revealed peak expression levels of these genes in the silk glands of fourth instar larvae. This integrative study enhances our understanding of the molecular mechanisms underlying silk production in P. xylostella and provides a foundation for future research into the biological roles, evolutionary trajectories, and potential applications of these silk fibroin genes in agricultural pest management and biotechnology. Full article

(This article belongs to the Special Issue Molecular Modeling: Latest Advances and Applications)

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27 pages, 16635 KiB

Open AccessArticle

Revealing the Role of Beesioside O from Actaea vaginata for the Treatment of Breast Cancer Using Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation

by Shuyang Li, Juan Lu, Hongwei Xue, Yang Lou, Jia Liu, Yutian Wang, Haifeng Wu and Xi Chen

Int. J. Mol. Sci. 2025, 26(5), 2283; https://doi.org/10.3390/ijms26052283 - 4 Mar 2025

Viewed by 763

Abstract

Breast cancer remains a leading cause of malignancy-related mortality among women, with rising global incidence. While surgical intervention is effective for early-stage breast cancer, drug therapy is indispensable, particularly for triple-negative breast cancer, where treatment options are still limited. Actaea vaginata, a traditional Chinese medicinal herb, has been historically applied for inflammatory conditions, including pharyngitis and stomatitis. However, its antitumor potential remains under-reported. In this study, a cycloartane triterpene saponin, beesioside O (BO), was isolated from this plant. Its antitumor activity was evaluated in vitro. Its potential therapeutic mechanisms were elucidated through network pharmacology. BO exhibited substantial potency in inhibiting breast cancer cells. Network pharmacology analysis uncovered 179 potential pharmacological targets of BO, which were predominantly concentrated in pathways, such as pathways in cancer, the PI3K-Akt signaling pathway, and chemical carcinogenesis receptor activation. Molecular docking analysis indicated that STAT3 exhibited minimal binding energy with BO. Additionally, molecular dynamics simulations verified the conformational stability of the BO-STAT3 complex. Western blot analysis demonstrated that STAT3 was downregulated following administration. These results imply that BO may exhibit a multi-target, synergistic therapeutic effect against breast cancer, with STAT3 recognized as a pivotal target. This study demonstrates the potential of BO for development as a chemotherapeutic agent for breast cancer treatment. It lays the groundwork for further exploration of BO’s bioactivity and provides valuable insights into its molecular mechanisms in breast cancer therapy. Full article

(This article belongs to the Special Issue Molecular Modeling: Latest Advances and Applications)

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14 pages, 1700 KiB

Open AccessArticle

miRNA-Based Diagnosis of Schizophrenia Using Machine Learning

by Vishrut Heda, Saanvi Dogra, Valentina L. Kouznetsova, Alex Kumar, Santosh Kesari and Igor F. Tsigelny

Int. J. Mol. Sci. 2025, 26(5), 2280; https://doi.org/10.3390/ijms26052280 - 4 Mar 2025

Viewed by 630

Abstract

Diagnostic practices for schizophrenia are unreliable due to the lack of a stable biomarker. However, machine learning holds promise in aiding in the diagnosis of schizophrenia and other neurological disorders. Dysregulated miRNAs were extracted from public sources. Datasets of miRNAs selected from the literature and random miRNAs with designated gene targets along with related pathways were assigned as descriptors of machine-learning models. These data were preprocessed and classified using WEKA and TensorFlow, and several classifiers were tested to train the model. The Sequential neural network developed by authors performed the best of the classifiers tested, achieving an accuracy of 94.32%. Naïve Bayes was the next best model, with an accuracy of 72.23%. MLP achieved an accuracy of 65.91%, followed by Hoeffding tree with an accuracy of 64.77%, Random tree with an accuracy of 63.64%, Random forest, which achieved an accuracy of 61.36%, and lastly ADABoostM1, which achieved an accuracy of 53.41%. The Sequential neural network and Naïve Bayes classifier were tested to validate the model as they achieved the highest accuracy. Naïve Bayes achieved a validation accuracy of 72.22%, whereas the sequential neural network achieved an accuracy of 88.88%. Our results demonstrate the practicality of machine learning in psychiatric diagnosis. Dysregulated miRNA combined with machine learning can serve as a diagnostic aid to physicians for schizophrenia and potentially other neurological disorders as well. Full article

(This article belongs to the Special Issue Molecular Modeling: Latest Advances and Applications)

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28 pages, 11579 KiB

Open AccessArticle

Identifying Exifone as a Dual-Target Agent Targeting Both SARS-CoV-2 3CL Protease and the ACE2/S-RBD Interaction Among Clinical Polyphenolic Compounds

by Jiani Lu, Yan Tang, Hongtao Li, Xixiang Chen, Pengcheng Qin, Jianrong Xu, Weihua Li and Lili Chen

Int. J. Mol. Sci. 2025, 26(5), 2243; https://doi.org/10.3390/ijms26052243 - 2 Mar 2025

Viewed by 1013

Abstract

The ongoing emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has led to resistance against multiple coronavirus disease 2019 (COVID-19) vaccines and therapeutic medications, making the development of effective therapeutics against SARS-CoV-2 a high priority. Studies have shown that bioactive polyphenols, particularly those with triphenol groups, can effectively inhibit the activity of SARS-CoV-2 3-chymotrypsin-like protease (3CL^pro). However, the structural instability of polyphenols necessitates further research. To address this, we conducted a literature review to identify triphenol compounds that are either approved or currently undergoing clinical trials, assessing their potential to inhibit SARS-CoV-2 3CL^pro. Exifone and benserazide hydrochloride were identified as the inhibitors of SARS-CoV-2 3CL^pro among these compounds, using a fluorescence resonance energy transfer (FRET)-based assay. Benserazide hydrochloride was confirmed as a covalent binder to SARS-CoV-2 3CL^pro through time-dependent inhibition and kinetic analysis, with its binding mode elucidated by molecular docking. Notably, exifone not only inhibited the protease activity but also blocked the interaction between the host cell receptor angiotensin-converting enzyme 2 (ACE2) and the SARS-CoV-2 spike protein receptor binding domain (S-RBD), as identified by surface plasmon resonance (SPR) and flow cytometry. Additionally, exifone demonstrated antiviral activity against various SARS-CoV-2-S pseudovirus variants. In conclusion, the discovery of exifone and benserazide hydrochloride underscores the potential of polyphenols in developing conserved 3CL^pro inhibitors for coronaviruses, offering new strategies for the rapid development of effective drugs against both current and future coronavirus pandemics. Full article

(This article belongs to the Special Issue Molecular Modeling: Latest Advances and Applications)

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22 pages, 3703 KiB

Open AccessArticle

Theoretical Study on the Metabolic Mechanism of Heptachlor in Human Cytochrome P450 Enzymes

by Xuerui Zhao, Hao Zhang, Xiaoli Shen, Qingchuan Zheng and Song Wang

Int. J. Mol. Sci. 2025, 26(5), 2021; https://doi.org/10.3390/ijms26052021 - 26 Feb 2025

Viewed by 345

Abstract

Heptachlor (HEP) is an insecticide metabolized by cytochrome P450 (CYP) enzymes in the human liver, resulting in the formation of heptachlor epoxide (HEPX). HEPX can persist in the human body for a long duration. Therefore, it can be extremely harmful. A comprehensive understanding of HEP’s metabolic fate may provide a theoretical basis for mitigating associated hazards. However, the specific human CYP isoforms that metabolize HEP, and their metabolic mechanisms, remain unclear. In this study, eight human CYP isoforms were used as catalytic enzymes to investigate the metabolic mechanism of HEP using molecular docking, molecular dynamics simulations, and quantum mechanical calculations. These results indicate that HEP primarily binds to CYP enzymes through hydrophobic interactions, and that the binding positions of HEP are determined by the composition and shape of the hydrophobic pockets near the active site. Based on the reaction distance, CYP2A6, CYP3A4, and CYP3A5 were the only three enzymes that could metabolize HEP. The epoxidation of HEP catalyzed by the doublet state of compound I was effectively concerted, and the rate-determining step was the electrophilic attack of the oxygen atom on HEP. The energy barriers of the rate-determining step vary significantly among different enzymes. A comparison of these energy barriers suggested that CYP3A5 is the most likely enzyme for HEP catalysis in humans. Full article

(This article belongs to the Special Issue Molecular Modeling: Latest Advances and Applications)

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19 pages, 5284 KiB

Open AccessArticle

Differential Inhibition by Cenobamate of Canonical Human Nav1.5 Ion Channels and Several Point Mutants

by Teodor Asvadur Şulea, Sorin Draga, Maria Mernea, Alexandru Dan Corlan, Beatrice Mihaela Radu, Andrei-Jose Petrescu and Bogdan Amuzescu

Int. J. Mol. Sci. 2025, 26(1), 358; https://doi.org/10.3390/ijms26010358 - 3 Jan 2025

Viewed by 1155

Abstract

Cenobamate is a new and highly effective antiseizure compound used for the treatment of adults with focal onset seizures and particularly for epilepsy resistant to other antiepileptic drugs. It acts on multiple targets, as it is a positive allosteric activator of γ-aminobutyric acid type A (GABA_A) receptors and an inhibitor of neuronal sodium channels, particularly of the late or persistent Na⁺ current. We recently evidenced the inhibitory effects of cenobamate on the peak and late current component of the human cardiac isoform hNav1.5. The determined apparent IC₅₀ values of 87.6 µM (peak) and 46.5 µM (late current) are within a clinically relevant range of concentrations (the maximal plasma therapeutic effective concentration for a daily dose of 400 mg in humans is 170 µM). In this study, we built a 3D model of the canonical hNav1.5 channel (UniProt Q14524-1) in open conformation using AlphaFold2, embedded it in a DPPC lipid bilayer, corrected the residue protonation state (pH 7.2) with H++, and added 2 Na⁺ ions in the selectivity filter. By molecular docking, we found the cenobamate binding site in the central cavity. We identified 10-point mutant variants in the binding site region and explored them via docking and MD. Mutants N1462K/Y (rs1064795922, rs199473614) and M1765R (rs752476527) (by docking) and N932S (rs2061582195) (by MD) featured higher predicted affinity than wild-type. Full article

(This article belongs to the Special Issue Molecular Modeling: Latest Advances and Applications)

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10 pages, 1029 KiB

Open AccessArticle

Theoretical Investigation of Electric Polarizability in Porphyrin–Zinc and Porphyrin–Zinc–Thiazole Complexes Using Small Property-Oriented Basis Sets

by Arkadiusz Kuziemski, Krzysztof Z. Łączkowski and Angelika Baranowska-Łączkowska

Int. J. Mol. Sci. 2024, 25(20), 11044; https://doi.org/10.3390/ijms252011044 - 14 Oct 2024

Viewed by 803

Abstract

Porphyrin complexes are of great importance due to their possible applications as sensors, solar cells and photocatalysts, as well as their ability to bind additional ligands. A valuable source of knowledge on their nature is their electric properties, which can be evaluated employing density functional theory (DFT) methods, supporting the experimental research. The present work aims at the application of small property-oriented basis sets in calculation of electric properties in transition metals, their oxides and test coordination complexes. Firstly, the existing polarized ZPol basis set for the first-row transition metals is modified in order to improve atomic polarizability results. For this purpose, optimization of the f-type polarization function exponent is carried out with respect to the value of average atomic polarizability of investigated metals. Next, both the original and the modified basis sets are employed in finite field CCSD(T) calculation of transition metal oxides’ dipole moments, as well as DFT calculation of polarizabilities in porphyrin–zinc and porphyrin–zinc–thiazole complexes. The obtained results show that the ZPol and ZPol-A basis sets can be successfully employed in the calculation of linear electric properties in large systems. The optimization procedure used in the present work can be employed for other source basis sets and elements, leading to new efficient polarized basis sets. Full article

(This article belongs to the Special Issue Molecular Modeling: Latest Advances and Applications)

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