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Biomolecules
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Nucleic Acids, Structure and Modeling
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Nucleic Acids, Structure and Modeling

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Natural and Bio-derived Molecules".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 22932

Special Issue Editor

Dr. Jiří Černý

E-Mail Website
Guest Editor
Institute of Biotechnology of the Czech Academy of Sciences, v. v. i., BIOCEV Research Center, Průmyslová 595, 252 50 Vestec, Czech Republic
Interests: understanding the structural and functional features of biologically relevant molecules and their interactions by employing the tools of structural bioinformatics and molecular modeling

Special Issue Information

Dear Colleagues,

Nucleic acids undoubtedly represent key biomolecular machinery. Their functional roles span from carrying the genetic information or regulating a wide range of biological processes to executing various chemical reactions. To cover all these roles, nucleic acids fold into intricate arrangements, changing their structure in response to the environment and performing their functions directly as isolated molecules or through interactions with other nucleic acids, small molecules, or proteins. The recent availability and ever-growing number of experimental structures containing nucleic acid molecules allows, in principle, a detailed understanding of their function at the atomic resolution level. The quality of available structures and of theoretical models is, however variable and, in many cases, does not allow to leverage the full potential of structural data.

The goal of this Special Issue of Biomolecules is to promote the field of structural biology of nucleic acids by critically assessing structural data and modeling tools. Especially welcome are studies employing the bioinformatics analysis of existing data concentrating on structural data annotation and validation, details of structurally or functionally interesting systems containing nucleic acids, reports on simulations reliably revealing the conformational variability, dynamics, and energy profiles during structural transitions and interactions of nucleic acids at a local or global level, and integrative approaches improving the structural information by synergy with various experimental and theoretical approaches.

Dr. Jiří Černý
Guest Editor

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. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • Nucleic acids
  • X-ray, cryoEM, or NMR structure
  • Structural bioinformatics
  • Molecular modeling
  • Molecular dynamics

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Published Papers (6 papers)

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Research

18 pages, 7705 KiB  
Article
A Virtual Screening Platform Identifies Chloroethylagelastatin A as a Potential Ribosomal Inhibitor
by Thomas R. Caulfield, Karen E. Hayes, Yushi Qiu, Mathew Coban, Joon Seok Oh, Amy L. Lane, Takehiko Yoshimitsu, Lori Hazlehurst, John A. Copland and Han W. Tun
Biomolecules 2020, 10(10), 1407; https://doi.org/10.3390/biom10101407 - 5 Oct 2020
Cited by 3 | Viewed by 2700
Abstract
Chloroethylagelastatin A (CEAA) is an analogue of agelastatin A (AA), a natural alkaloid derived from a marine sponge. It is under development for therapeutic use against brain tumors as it has excellent central nervous system (CNS) penetration and pre-clinical therapeutic activity against brain [...] Read more.
Chloroethylagelastatin A (CEAA) is an analogue of agelastatin A (AA), a natural alkaloid derived from a marine sponge. It is under development for therapeutic use against brain tumors as it has excellent central nervous system (CNS) penetration and pre-clinical therapeutic activity against brain tumors. Recently, AA was shown to inhibit protein synthesis by binding to the ribosomal A-site. In this study, we developed a novel virtual screening platform to perform a comprehensive screening of various AA analogues showing that AA analogues with proven therapeutic activity including CEAA have significant ribosomal binding capacity whereas therapeutically inactive analogues show poor ribosomal binding and revealing structural fingerprint features essential for drug-ribosome interactions. In particular, CEAA was found to have greater ribosomal binding capacity than AA. Biological tests showed that CEAA binds the ribosome and contributes to protein synthesis inhibition. Our findings suggest that CEAA may possess ribosomal inhibitor activity and that our virtual screening platform may be a useful tool in discovery and development of novel ribosomal inhibitors. Full article
(This article belongs to the Special Issue Nucleic Acids, Structure and Modeling)
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16 pages, 1955 KiB  
Article
A Fluorescent Assay to Search for Inhibitors of HIV-1 Integrase Interactions with Human Ku70 Protein, and Its Application for Characterization of Oligonucleotide Inhibitors
by Simon Galkin, Anna Rozina, Arthur Zalevsky, Marina Gottikh and Andrey Anisenko
Biomolecules 2020, 10(9), 1236; https://doi.org/10.3390/biom10091236 - 25 Aug 2020
Cited by 2 | Viewed by 3684
Abstract
The search for compounds that can inhibit the interaction of certain viral proteins with their cellular partners is a promising trend in the development of antiviral drugs. We have previously shown that binding of HIV-1 integrase with human Ku70 protein is essential for [...] Read more.
The search for compounds that can inhibit the interaction of certain viral proteins with their cellular partners is a promising trend in the development of antiviral drugs. We have previously shown that binding of HIV-1 integrase with human Ku70 protein is essential for viral replication. Here, we present a novel, cheap, and fast assay to search for inhibitors of these proteins’ binding based on the usage of genetically encoded fluorescent tags linked to both integrase and Ku70. Using this approach, we have elucidated structure-activity relationships for a set of oligonucleotide conjugates with eosin and shown that their inhibitory activity is primarily achieved through interactions between the conjugate nucleic bases and integrase. Molecular modeling of HIV-1 integrase in complex with the conjugates suggests that they can shield E212/L213 residues in integrase, which are crucial for its efficient binding to Ku70, in a length-dependent manner. Using the developed system, we have found the 11-mer phosphorothioate bearing 3’-end eosin-Y to be the most efficient inhibitor among the tested conjugates. Full article
(This article belongs to the Special Issue Nucleic Acids, Structure and Modeling)
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10 pages, 1337 KiB  
Article
Tautomerism of Guanine Analogues
by Jakub Radek Štoček and Martin Dračínský
Biomolecules 2020, 10(2), 170; https://doi.org/10.3390/biom10020170 - 22 Jan 2020
Cited by 8 | Viewed by 4878
Abstract
Tautomerism of nucleic acid (NA) bases is a crucial factor for the maintenance and translation of genetic information in organisms. Only canonical tautomers of NA bases can form hydrogen-bonded complexes with their natural counterparts. On the other hand, rare tautomers of nucleobases have [...] Read more.
Tautomerism of nucleic acid (NA) bases is a crucial factor for the maintenance and translation of genetic information in organisms. Only canonical tautomers of NA bases can form hydrogen-bonded complexes with their natural counterparts. On the other hand, rare tautomers of nucleobases have been proposed to be involved in processes catalysed by NA enzymes. Isocytosine, which can be considered as a structural fragment of guanine, is known to have two stable tautomers both in solution and solid states. The tautomer equilibrium of isocytosine contrasts with the remarkable stability of the canonical tautomer of guanine. This paper investigates the factors contributing to the stability of the canonical tautomer of guanine by a combination of NMR experiments and theoretical calculations. The electronic effects of substituents on the stability of the rare tautomers of isocytosine and guanine derivatives are studied by density functional theory (DFT) calculations. Selected derivatives are studied by variable-temperature NMR spectroscopy. Rare tautomers can be stabilised in solution by intermolecular hydrogen-bonding interactions with suitable partners. These intermolecular interactions give rise to characteristic signals in proton NMR spectra, which make it possible to undoubtedly confirm the presence of a rare tautomer. Full article
(This article belongs to the Special Issue Nucleic Acids, Structure and Modeling)
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14 pages, 3739 KiB  
Article
Molecular Dynamics Simulations Suggest a Non-Doublet Decoding Model of −1 Frameshifting by tRNASer3
by Thomas Caulfield, Matt Coban, Alex Tek and Samuel Coulbourn Flores
Biomolecules 2019, 9(11), 745; https://doi.org/10.3390/biom9110745 - 18 Nov 2019
Cited by 9 | Viewed by 3444
Abstract
In-frame decoding in the ribosome occurs through canonical or wobble Watson–Crick pairing of three mRNA codon bases (a triplet) with a triplet of anticodon bases in tRNA. Departures from the triplet–triplet interaction can result in frameshifting, meaning downstream mRNA codons are then read [...] Read more.
In-frame decoding in the ribosome occurs through canonical or wobble Watson–Crick pairing of three mRNA codon bases (a triplet) with a triplet of anticodon bases in tRNA. Departures from the triplet–triplet interaction can result in frameshifting, meaning downstream mRNA codons are then read in a different register. There are many mechanisms to induce frameshifting, and most are insufficiently understood. One previously proposed mechanism is doublet decoding, in which only codon bases 1 and 2 are read by anticodon bases 34 and 35, which would lead to −1 frameshifting. In E. coli, tRNASer3GCU can induce −1 frameshifting at alanine (GCA) codons. The logic of the doublet decoding model is that the Ala codon’s GC could pair with the tRNASer3′s GC, leaving the third anticodon residue U36 making no interactions with mRNA. Under that model, a U36C mutation would still induce −1 frameshifting, but experiments refute this. We perform all-atom simulations of wild-type tRNASer3, as well as a U36C mutant. Our simulations revealed a hydrogen bond between U36 of the anticodon and G1 of the codon. The U36C mutant cannot make this interaction, as it lacks the hydrogen-bond-donating H3. The simulation thus suggests a novel, non-doublet decoding mechanism for −1 frameshifting by tRNASer3 at Ala codons. Full article
(This article belongs to the Special Issue Nucleic Acids, Structure and Modeling)
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17 pages, 4022 KiB  
Article
Dynamic DNA Energy Landscapes and Substrate Complexity in Triplet Repeat Expansion and DNA Repair
by Jens Völker, G. Eric Plum, Vera Gindikin and Kenneth J. Breslauer
Biomolecules 2019, 9(11), 709; https://doi.org/10.3390/biom9110709 - 6 Nov 2019
Cited by 8 | Viewed by 3415
Abstract
DNA repeat domains implicated in DNA expansion diseases exhibit complex conformational and energy landscapes that impact biological outcomes. These landscapes include ensembles of entropically driven positional interchanges between isoenergetic, isomeric looped states referred to as rollamers. Here, we present evidence for the position-dependent [...] Read more.
DNA repeat domains implicated in DNA expansion diseases exhibit complex conformational and energy landscapes that impact biological outcomes. These landscapes include ensembles of entropically driven positional interchanges between isoenergetic, isomeric looped states referred to as rollamers. Here, we present evidence for the position-dependent impact on repeat DNA energy landscapes of an oxidative lesion (8oxodG) and of an abasic site analogue (tetrahydrofuran, F), the universal intermediate in base excision repair (BER). We demonstrate that these lesions modulate repeat bulge loop distributions within the wider dynamic rollamer triplet repeat landscapes. We showed that the presence of a lesion disrupts the energy degeneracy of the rollameric positional isomers. This lesion-induced disruption leads to the redistribution of loop isomers within the repeat loop rollamer ensemble, favoring those rollameric isomers where the lesion is positioned to be energetically least disruptive. These dynamic ensembles create a highly complex energy/conformational landscape of potential BER enzyme substrates to select for processing or to inhibit processing. We discuss the implications of such lesion-induced alterations in repeat DNA energy landscapes in the context of potential BER repair outcomes, thereby providing a biophysical basis for the intriguing in vivo observation of a linkage between pathogenic triplet repeat expansion and DNA repair. Full article
(This article belongs to the Special Issue Nucleic Acids, Structure and Modeling)
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21 pages, 3935 KiB  
Article
MS-Based Approaches Enable the Structural Characterization of Transcription Factor/DNA Response Element Complex
by Lukáš Slavata, Josef Chmelík, Daniel Kavan, Růžena Filandrová, Jan Fiala, Michal Rosůlek, Hynek Mrázek, Zdeněk Kukačka, Karel Vališ, Petr Man, Michael Miller, William McIntyre, Daniele Fabris and Petr Novák
Biomolecules 2019, 9(10), 535; https://doi.org/10.3390/biom9100535 - 26 Sep 2019
Cited by 10 | Viewed by 3833
Abstract
The limited information available on the structure of complexes involving transcription factors and cognate DNA response elements represents a major obstacle in the quest to understand their mechanism of action at the molecular level. We implemented a concerted structural proteomics approach, which combined [...] Read more.
The limited information available on the structure of complexes involving transcription factors and cognate DNA response elements represents a major obstacle in the quest to understand their mechanism of action at the molecular level. We implemented a concerted structural proteomics approach, which combined hydrogen-deuterium exchange (HDX), quantitative protein-protein and protein-nucleic acid cross-linking (XL), and homology analysis, to model the structure of the complex between the full-length DNA binding domain (DBD) of Forkhead box protein O4 (FOXO4) and its DNA binding element (DBE). The results confirmed that FOXO4-DBD assumes the characteristic forkhead topology shared by these types of transcription factors, but its binding mode differs significantly from those of other members of the family. The results showed that the binding interaction stabilized regions that were rather flexible and disordered in the unbound form. Surprisingly, the conformational effects were not limited only to the interface between bound components, but extended also to distal regions that may be essential to recruiting additional factors to the transcription machinery. In addition to providing valuable new insights into the binding mechanism, this project provided an excellent evaluation of the merits of structural proteomics approaches in the investigation of systems that are not directly amenable to traditional high-resolution techniques. Full article
(This article belongs to the Special Issue Nucleic Acids, Structure and Modeling)
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