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Advances in Modelling and Simulations of Anionic Molecules
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Advances in Modelling and Simulations of Anionic Molecules

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 (30 September 2021) | Viewed by 12681

Special Issue Editors

Dr. Neha S. Gandhi

E-Mail Website
Guest Editor
School of Mathematical Sciences, Faculty of Science and Engineering, Queensland University of Technology, 2 George Street, Brisbane, QLD-4000, Australia
Interests: structural bioinformatics; molecular docking; molecular dynamics; glycobiology; protein structure; protein folding and aggregation; ligand–protein/nucleotide and protein–protein interactions; post-translation modification of proteins
Dr. Pramod Nair

E-Mail Website
Guest Editor
Department of Clinical Pharmacology, Flinders Health and Medical Research Institute, Flinders University College of Medicine and Public Health, Flinders Medical Centre, Bedford Park, SA 5042, Australia
Interests: drug design and discovery; molecular dynamics simulations; drug metabolism; anticancer agents
Dr. Zak Hughes

E-Mail Website
Guest Editor
School of Chemistry and Biosciences, University of Bradford, Bradford BD7 1DP, UK
Interests: molecular simulation of biomolecules; biomolecule–nanomaterial interactions; protein/structure predicton; molecular simulation of intrinsically disordered peptides; biomolecule–surface interactions

Special Issue Information

Dear Colleagues,

Negatively charged or anionic molecules are found in numerous species and play an important role in various biological functions. The basic unit of life, DNA, is negatively charged due to the presence of a phosphate–sugar backbone, thus rendering DNA less vulnerable to nucleophilic attack, imparting a stable structure, and allowing histones to join DNA and exert their key regulating functions. Other examples include phosphorylation of serine and threonine residues, a major post-translational modification (PTMs) found in the 21,000 proteins encoded by the human genome. These PTMs play an important role in most cellular processes, such as protein synthesis, cell division, signal transduction, cell growth, development, and ageing. Phosphorylation and sulphation present on carbohydrate moieties of glycoproteins and proteoglycans such as glycosaminoglycans also cause different biological responses. As promising biomolecule carriers, negatively charged nanoparticles have a stronger interaction with zwitterionic membranes (vesicles or liposomes). Negative charge can affect the secondary structure, solubility in lipids, and aggregation of biomolecules. Despite electrostatic issues with the charges, molecular modelling techniques like docking and molecular dynamics have become a powerful tool in the identification and characterization of the structure–activity relationship of these anionic molecules in recent years.

This Special Issue of the International Journal of Molecular Sciences will discuss and offer recent advances into modelling and simulations to decipher the structure, function, interactions, and mechanisms of all types of negatively charged molecules, such as sulphated glycosaminoglycans, glucuronides, nucleotide molecules like DNA and RNA, negatively charged lipids and nanoparticles, and phosphorylated proteins. Manuscripts such as short communications, original research papers, and reviews from researchers in these fields are welcome to provide an overview of the newest findings and the future of modelling of anionic molecules.

Dr. Neha S. Gandhi
Dr. Pramod Nair
Dr. Zak Hughes
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

  • sulphated glycosaminoglycans
  • nucleotides
  • anionic transport
  • anionic lipids
  • anionic sugars
  • post-translational modifications (phosphorylation)
  • negatively charged nanoparticles
  • anionic molecules in human health
  • the structure of anionic molecules
  • molecular modelling
  • molecular dynamics

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Published Papers (4 papers)

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Research

25 pages, 4284 KiB  
Article
Design and Characterization of a Cell-Penetrating Peptide Derived from the SOX2 Transcription Factor
by Neha S. Gandhi, Edina Wang, Anabel Sorolla, Yu Jie Kan, Adil Malik, Jyotsna Batra, Kimberly A. Young, Wan Jun Tie, Pilar Blancafort and Ricardo L. Mancera
Int. J. Mol. Sci. 2021, 22(17), 9354; https://doi.org/10.3390/ijms22179354 - 28 Aug 2021
Cited by 5 | Viewed by 3704
Abstract
SOX2 is an oncogenic transcription factor overexpressed in nearly half of the basal-like triple-negative breast cancers associated with very poor outcomes. Targeting and inhibiting SOX2 is clinically relevant as high SOX2 mRNA levels are positively correlated with decreased overall survival and progression-free survival [...] Read more.
SOX2 is an oncogenic transcription factor overexpressed in nearly half of the basal-like triple-negative breast cancers associated with very poor outcomes. Targeting and inhibiting SOX2 is clinically relevant as high SOX2 mRNA levels are positively correlated with decreased overall survival and progression-free survival in patients affected with breast cancer. Given its key role as a master regulator of cell proliferation, SOX2 represents an important scaffold for the engineering of dominant-negative synthetic DNA-binding domains (DBDs) that act by blocking or interfering with the oncogenic activity of the endogenous transcription factor in cancer cells. We have synthesized an interference peptide (iPep) encompassing a truncated 24 amino acid long C-terminus of SOX2 containing a potential SOX-specific nuclear localization sequence, and the determinants of the binding of SOX2 to the DNA and to its transcription factor binding partners. We found that the resulting peptide (SOX2-iPep) possessed intrinsic cell penetration and promising nuclear localization into breast cancer cells, and decreased cellular proliferation of SOX2 overexpressing cell lines. The novel SOX2-iPep was found to exhibit a random coil conformation predominantly in solution. Molecular dynamics simulations were used to characterize the interactions of both the SOX2 transcription factor and the SOX2-iPep with FGF4-enhancer DNA in the presence of the POU domain of the partner transcription factor OCT4. Predictions of the free energy of binding revealed that the iPep largely retained the binding affinity for DNA of parental SOX2. This work will enable the future engineering of novel dominant interference peptides to transport different therapeutic cargo molecules such as anti-cancer drugs into cells. Full article
(This article belongs to the Special Issue Advances in Modelling and Simulations of Anionic Molecules)
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9 pages, 9326 KiB  
Article
Effect of Polyphosphorylation on Behavior of Protein Disordered Regions
by Pavel I. Semenyuk
Int. J. Mol. Sci. 2021, 22(15), 7883; https://doi.org/10.3390/ijms22157883 - 23 Jul 2021
Cited by 2 | Viewed by 2512
Abstract
Proteins interact with many charged biological macromolecules (polyelectrolytes), including inorganic polyphosphates. Recently a new protein post-translational modification, polyphosphorylation, or a covalent binding of polyphosphate chain to lysine, was demonstrated in human and yeast. Herein, we performed the first molecular modeling study of a [...] Read more.
Proteins interact with many charged biological macromolecules (polyelectrolytes), including inorganic polyphosphates. Recently a new protein post-translational modification, polyphosphorylation, or a covalent binding of polyphosphate chain to lysine, was demonstrated in human and yeast. Herein, we performed the first molecular modeling study of a possible effect of polyphosphorylation on behavior of the modified protein using replica exchange molecular dynamics simulations in atomistic force field with explicit water. Human endoplasmin (GRP-94), a member of heat shock protein 90 family, was selected as a model protein. Intrinsically disordered region in N-terminal domain serving as a charged linker between domains and containing a polyacidic serine and lysine-rich motif, was selected as a potent polyphosphorylation site according to literature data. Polyphosphorylation, depending on exact modification site, has been shown to influence on the disordered loop flexibility and induce its further expanding, as well as induce changes in interaction with ordered part of the molecule. As a result, polyphosphorylation in N-terminal domain might affect interaction of HSP90 with client proteins since these chaperones play a key role in protein folding. Full article
(This article belongs to the Special Issue Advances in Modelling and Simulations of Anionic Molecules)
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18 pages, 4957 KiB  
Article
Combinatorial Virtual Library Screening Study of Transforming Growth Factor-β2–Chondroitin Sulfate System
by Nehru Viji Sankaranarayanan, Balaji Nagarajan and Umesh R. Desai
Int. J. Mol. Sci. 2021, 22(14), 7542; https://doi.org/10.3390/ijms22147542 - 14 Jul 2021
Cited by 9 | Viewed by 2337
Abstract
Transforming growth factor-beta (TGF-β), a member of the TGF-β cytokine superfamily, is known to bind to sulfated glycosaminoglycans (GAGs), but the nature of this interaction remains unclear. In a recent study, we found that preterm human milk TGF-β2 is sequestered by chondroitin sulfate [...] Read more.
Transforming growth factor-beta (TGF-β), a member of the TGF-β cytokine superfamily, is known to bind to sulfated glycosaminoglycans (GAGs), but the nature of this interaction remains unclear. In a recent study, we found that preterm human milk TGF-β2 is sequestered by chondroitin sulfate (CS) in its proteoglycan form. To understand the molecular basis of the TGF-β2–CS interaction, we utilized the computational combinatorial virtual library screening (CVLS) approach in tandem with molecular dynamics (MD) simulations. All possible CS oligosaccharides were generated in a combinatorial manner to give 24 di- (CS02), 192 tetra- (CS04), and 1536 hexa- (CS06) saccharides. This library of 1752 CS oligosaccharides was first screened against TGF-β2 using the dual filter CVLS algorithm in which the GOLDScore and root-mean-square-difference (RMSD) between the best bound poses were used as surrogate markers for in silico affinity and in silico specificity. CVLS predicted that both the chain length and level of sulfation are critical for the high affinity and high specificity recognition of TGF-β2. Interestingly, CVLS led to identification of two distinct sites of GAG binding on TGF-β2. CVLS also deduced the preferred composition of the high specificity hexasaccharides, which were further assessed in all-atom explicit solvent MD simulations. The MD results confirmed that both sites of binding form stable GAG–protein complexes. More specifically, the highly selective CS chains were found to engage the TGF-β2 monomer with high affinity. Overall, this work present key principles of recognition with regard to the TGF-β2–CS system. In the process, it led to the generation of the in silico library of all possible CS oligosaccharides, which can be used for advanced studies on other protein–CS systems. Finally, the study led to the identification of unique CS sequences that are predicted to selectively recognize TGF-β2 and may out-compete common natural CS biopolymers. Full article
(This article belongs to the Special Issue Advances in Modelling and Simulations of Anionic Molecules)
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15 pages, 2572 KiB  
Article
Multiscale Modeling of Wobble to Watson–Crick-Like Guanine–Uracil Tautomerization Pathways in RNA
by Shreya Chandorkar, Shampa Raghunathan, Tanashree Jaganade and U. Deva Priyakumar
Int. J. Mol. Sci. 2021, 22(11), 5411; https://doi.org/10.3390/ijms22115411 - 21 May 2021
Cited by 7 | Viewed by 2923
Abstract
Energetically unfavorable Watson–Crick (WC)-like tautomeric forms of nucleobases are known to introduce spontaneous mutations, and contribute to replication, transcription, and translation errors. Recent NMR relaxation dispersion techniques were able to show that wobble (w) G•U mispair exists in equilibrium with the short-lived, low-population [...] Read more.
Energetically unfavorable Watson–Crick (WC)-like tautomeric forms of nucleobases are known to introduce spontaneous mutations, and contribute to replication, transcription, and translation errors. Recent NMR relaxation dispersion techniques were able to show that wobble (w) G•U mispair exists in equilibrium with the short-lived, low-population WC-like enolic tautomers. Presently, we have investigated the wG•U → WC-like enolic reaction pathway using various theoretical methods: quantum mechanics (QM), molecular dynamics (MD), and combined quantum mechanics/molecular mechanics (QM/MM). The previous studies on QM gas phase calculations were inconsistent with experimental data. We have also explored the environmental effects on the reaction energies by adding explicit water. While the QM-profile clearly becomes endoergic in the presence of water, the QM/MM-profile remains consistently endoergic in the presence and absence of water. Hence, by including microsolvation and QM/MM calculations, the experimental data can be explained. For the G•Uenol→ Genol•U pathway, the latter appears to be energetically more favorable throughout all computational models. This study can be considered as a benchmark of various computational models of wG•U to WC-like tautomerization pathways with and without the environmental effects, and may contribute on further studies of other mispairs as well. Full article
(This article belongs to the Special Issue Advances in Modelling and Simulations of Anionic Molecules)
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