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Biophysics of Nucleic Acids Celebrating the 75th Birthday of Professor...
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Biophysics of Nucleic Acids Celebrating the 75th Birthday of Professor Kenneth J. Breslauer

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Biochemistry, Biophysics and Computational Biology".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 44591

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Tigran Chalikian

E-Mail Website
Guest Editor
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada
Interests: physico-chemical properties of proteins and nucleic acids; protein and nucleic acid recognition events; noncanonical nucleic acid structures; thermodynamics; solvation; volumetric properties of biological systems; optical spectroscopy
Dr. Jens Völker

E-Mail Website
Guest Editor
Department of Chemistry and Chemical Biology; Rutgers, The State University of New Jersey, New Brunswick, NJ 07102, USA
Interests: DNA; structure; thermodynamics; molecular biophysics

Special Issue Information

Dear Colleagues,

This Special Issue celebrates the seminal contributions of Professor Kenneth J. Breslauer to the field of DNA and RNA biophysics during more than five decades of his service to science, and is dedicated to the 75th anniversary of his birthday. In addition to being one of the most important classes of molecules of life, nucleic acids are an exciting and exceedingly rewarding subject for biophysical research. The polymorphic nature of DNA and RNA, their conformational flexibility, responsiveness to subtle changes in chemical environment, and multiplicity and combinatorial diversity of their recognition sites render these molecules not just a reservoir of genetic information but also important elements of control in a myriad of cellular events. More recently, nucleic acids have increasingly been used as structural building blocks in nanotechnological applications. Notwithstanding the seventy years of intensive research since the discovery of the double helix, DNA continues to remain very much an enigma, making it a fertile ground for biophysical studies. In one particular development, multidisciplinary research into noncanonical DNA and RNA structures has produced an increasing body of evidence underscoring their biological roles and association with disease. A major and still elusive goal of biophysical research is to develop predictive algorithms to evaluate the sequence-specific, interacting partner-specific, and local environment-specific conformational preferences of functionally important domains within the genome and to selectively modulate these preferences in a controlled manner by low-molecular-weight ligands.

This Special Issue plans to publish a wide selection of papers on fundamental physical, chemical, and biological properties of canonical and noncanonical nucleic acid structures; their recognition by ligands, proteins, and other nucleic acids; their role in cellular events; as well as biotechnological and pharmaceutical applications. Particular emphasis will be placed on the evolutionary progress from in vitro studies of intentionally simplified DNA and RNA models in dilute solutions to in vivo studies of extremely intricate nucleic acid complexes in the crowded environment of the cell. Submissions are open to both theoretical and experimental scientists. Contributions can be original research papers, reviews, perspectives, personal reminiscences associated with interactions/associations with Professor Kenneth J. Breslauer, or a hybrid of these formats. Contributions solely containing personal reminiscences will be collected in an extended Editorial.

Prof. Dr. Tigran Chalikian
Dr. Jens Völker
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. Life 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 2600 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

  • DNA and RNA 
  • noncanonical structures
  • thermodynamics and kinetics
  • molecular recognition
  • biological function and disease
  • DNA nanotechnology

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Published Papers (16 papers)

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Editorial

Jump to: Research, Review

16 pages, 231 KiB  
Editorial
Tribute to Kenneth J. Breslauer
by Tigran V. Chalikian
Life 2022, 12(9), 1325; https://doi.org/10.3390/life12091325 - 27 Aug 2022
Viewed by 1646
Abstract
It is an exciting experience to serve as guest editor for a Special Issue celebrating the 75th birthday of Professor Kenneth J [...] Full article
(This article belongs to the Special Issue Biophysics of Nucleic Acids Celebrating the 75th Birthday of Professor Kenneth J. Breslauer)

Research

Jump to: Editorial, Review

28 pages, 3435 KiB  
Article
Characterization of Aurintricarboxylic Acid (ATA) Interactions with Plasma Transporter Protein and SARS-CoV-2 Viral Targets: Correlation of Functional Activity and Binding Energetics
by Conceição A. Minetti, David P. Remeta, Keiji Hashimoto, Radha Bonala, Rajesh Chennamshetti, Xingyu Yin, Miguel Garcia-Diaz, Arthur P. Grollman, Francis Johnson and Viktoriya S. Sidorenko
Life 2022, 12(6), 872; https://doi.org/10.3390/life12060872 - 10 Jun 2022
Cited by 5 | Viewed by 2976
Abstract
In an effort to identify functional-energetic correlations leading to the development of efficient anti-SARS-CoV-2 therapeutic agents, we have designed synthetic analogs of aurintricarboxylic acid (ATA), a heterogeneous polymeric mixture of structurally related linear homologs known to exhibit a host of biological properties, including [...] Read more.
In an effort to identify functional-energetic correlations leading to the development of efficient anti-SARS-CoV-2 therapeutic agents, we have designed synthetic analogs of aurintricarboxylic acid (ATA), a heterogeneous polymeric mixture of structurally related linear homologs known to exhibit a host of biological properties, including antiviral activity. These derivatives are evaluated for their ability to interact with a plasma transporter protein (human serum albumin), eukaryotic (yeast) ribosomes, and a SARS-CoV-2 target, the RNA-dependent RNA polymerase (RdRp). The resultant data are critical for characterizing drug distribution, bioavailability, and effective inhibition of host and viral targets. Promising lead compounds are selected on the basis of their binding energetics which have been characterized and correlated with functional activities as assessed by inhibition of RNA replication and protein synthesis. Our results reveal that the activity of heterogeneous ATA is mimicked by linear compounds of defined molecular weight, with a dichlorohexamer salicylic-acid derivative exhibiting the highest potency. These findings are instrumental for optimizing the design of structurally defined ATA analogs that fulfill the requirements of an antiviral drug with respect to bioavailability, homogeneity, and potency, thereby expanding the arsenal of therapeutic regimens that are currently available to address the urgent need for effective SARS-CoV-2 treatment strategies. Full article
(This article belongs to the Special Issue Biophysics of Nucleic Acids Celebrating the 75th Birthday of Professor Kenneth J. Breslauer)
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Graphical abstract

15 pages, 2710 KiB  
Article
Thermally Induced Transitions of d(G4T4G3) Quadruplexes Can Be Described as Kinetically Driven Processes
by Iztok Prislan, Tomaz Urbic and Natasa Poklar Ulrih
Life 2022, 12(6), 825; https://doi.org/10.3390/life12060825 - 1 Jun 2022
Cited by 1 | Viewed by 1745
Abstract
DNA sequences that are rich in guanines and can form four-stranded structures are called G-quadruplexes. Due to the growing evidence that they may play an important role in several key biological processes, the G-quadruplexes have captured the interest of several researchers. G-quadruplexes may [...] Read more.
DNA sequences that are rich in guanines and can form four-stranded structures are called G-quadruplexes. Due to the growing evidence that they may play an important role in several key biological processes, the G-quadruplexes have captured the interest of several researchers. G-quadruplexes may form in the presence of different metal cations as polymorphic structures formed in kinetically governed processes. Here we investigate a complex polymorphism of d(G4T4G3) quadruplexes at different K+ concentrations. We show that population size of different d(G4T4G3) quadruplex conformations can be manipulated by cooling rate and/or K+ concentration. We use a kinetic model to describe data obtained from DSC, CD and UV spectroscopy and PAGE experiments. Our model is able to describe the observed thermally induced conformational transitions of d(G4T4G3) quadruplexes at different K+ concentrations. Full article
(This article belongs to the Special Issue Biophysics of Nucleic Acids Celebrating the 75th Birthday of Professor Kenneth J. Breslauer)
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8 pages, 898 KiB  
Article
The Pressure Dependence of the Stability of the G-quadruplex Formed by d(TGGGGT)
by Nabeel Tariq, Takuma Kume, Ujala N. Feroze and Robert B. Macgregor, Jr.
Life 2022, 12(5), 765; https://doi.org/10.3390/life12050765 - 21 May 2022
Cited by 1 | Viewed by 2220
Abstract
The G-quadruplex (GQ), a tetrahelix formed by guanine-rich nucleic acid sequences, is a potential drug target for several diseases. Monomolecular GQs are stabilized by guanine tetrads and non-guanine regions that form loops. Hydrostatic pressure destabilizes the folded, monomolecular GQ structures. In this communication, [...] Read more.
The G-quadruplex (GQ), a tetrahelix formed by guanine-rich nucleic acid sequences, is a potential drug target for several diseases. Monomolecular GQs are stabilized by guanine tetrads and non-guanine regions that form loops. Hydrostatic pressure destabilizes the folded, monomolecular GQ structures. In this communication, we present data on the effect of pressure on the conformational stability of the tetramolecular GQ, d[5′-TGGGGT-3′]4. This molecule does not have loops linking the tetrads; thus, its physical properties presumably reflect those of the tetrads alone. Understanding the properties of the tetrads will aid in understanding the contribution of the other structural components to the stability of GQ DNA. By measuring UV light absorption, we have studied the effect of hydrostatic pressure on the thermal stability of the tetramolecular d[5′-TGGGGT-3′]4 in the presence of sodium ions. Our data show that, unlike monomolecular GQ, the temperature at which d[5′-TGGGGT-3′]4 dissociates to form the constituent monomers is nearly independent of pressure up to 200 MPa. This implies that there is no net molar volume difference (∆V) between the GQ and the unfolded random-coil states. This finding further suggests that the large negative ∆V values for the unfolding of monomolecular GQ are due to the presence of the loop regions in those structures. Full article
(This article belongs to the Special Issue Biophysics of Nucleic Acids Celebrating the 75th Birthday of Professor Kenneth J. Breslauer)
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16 pages, 6846 KiB  
Article
Revisiting DNA Sequence-Dependent Deformability in High-Resolution Structures: Effects of Flanking Base Pairs on Dinucleotide Morphology and Global Chain Configuration
by Robert T. Young, Luke Czapla, Zoe O. Wefers, Benjamin M. Cohen and Wilma K. Olson
Life 2022, 12(5), 759; https://doi.org/10.3390/life12050759 - 20 May 2022
Cited by 8 | Viewed by 3817
Abstract
DNA carries more than the list of biochemical ingredients that drive the basic functions of living systems. The sequence of base pairs includes a multitude of structural and energetic signals, which determine the degree to which the long, threadlike molecule moves and how [...] Read more.
DNA carries more than the list of biochemical ingredients that drive the basic functions of living systems. The sequence of base pairs includes a multitude of structural and energetic signals, which determine the degree to which the long, threadlike molecule moves and how it responds to proteins and other molecules that control its processing and govern its packaging. The chemical composition of base pairs directs the spatial disposition and fluctuations of successive residues. The observed arrangements of these moieties in high-resolution protein–DNA crystal structures provide one of the best available estimates of the natural, sequence-dependent structure and deformability of the double-helical molecule. Here, we update the set of knowledge-based elastic potentials designed to describe the observed equilibrium structures and configurational fluctuations of the ten unique base-pair steps. The large number of currently available structures makes it possible to characterize the configurational preferences of the DNA base-pair steps within the context of their immediate neighbors, i.e., tetrameric context. Use of these knowledge-based potentials shows promise in accounting for known effects of sequence in long chain molecules, e.g., the degree of curvature reported in classic gel mobility studies and the recently reported sequence-dependent responses of supercoiled minicircles to nuclease cleavage. Full article
(This article belongs to the Special Issue Biophysics of Nucleic Acids Celebrating the 75th Birthday of Professor Kenneth J. Breslauer)
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17 pages, 2184 KiB  
Article
The Bootstrap Model of Prebiotic Networks of Proteins and Nucleic Acids
by Thomas Farquharson, Luca Agozzino and Ken Dill
Life 2022, 12(5), 724; https://doi.org/10.3390/life12050724 - 12 May 2022
Cited by 1 | Viewed by 2160
Abstract
It is not known how life arose from prebiotic physical chemistry. How did fruitful cell-like associations emerge from the two polymer types—informational (nucleic acids, xNAs = DNA or RNA) and functional (proteins)? Our model shows how functional networks could bootstrap from random sequence-independent [...] Read more.
It is not known how life arose from prebiotic physical chemistry. How did fruitful cell-like associations emerge from the two polymer types—informational (nucleic acids, xNAs = DNA or RNA) and functional (proteins)? Our model shows how functional networks could bootstrap from random sequence-independent initial states. For proteins, we adopt the foldamer hypothesis: through persistent nonequilibrium prebiotic syntheses, short random peptides fold and catalyze the elongation of others. The xNAs enter through random binding to the peptides, and all chains can mutate. Chains grow inside colloids that split when they’re large, coupling faster growth speeds to bigger populations. Random and useless at first, these folding and binding events grow protein—xNA networks that resemble today’s protein–protein networks. Full article
(This article belongs to the Special Issue Biophysics of Nucleic Acids Celebrating the 75th Birthday of Professor Kenneth J. Breslauer)
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13 pages, 2520 KiB  
Article
The Effects of Flexibility on dsDNA–dsDNA Interactions
by Chuanying Chen and B. Montgomery Pettitt
Life 2022, 12(5), 699; https://doi.org/10.3390/life12050699 - 7 May 2022
Cited by 1 | Viewed by 2199
Abstract
A detailed understanding of the physical mechanism of ion-mediated dsDNA interactions is important in biological functions such as DNA packaging and homologous pairing. We report the potential of mean force (PMF) or the effective solvent mediated interactions between two parallel identical dsDNAs as [...] Read more.
A detailed understanding of the physical mechanism of ion-mediated dsDNA interactions is important in biological functions such as DNA packaging and homologous pairing. We report the potential of mean force (PMF) or the effective solvent mediated interactions between two parallel identical dsDNAs as a function of interhelical separation in 0.15 M NaCl solution. Here, we study the influence of flexibility of dsDNAs on the effective interactions by comparing PMFs between rigid models and flexible ones. The role of flexibility of dsDNA pairs in their association is elucidated by studying the energetic properties of Na+ ions as well as the fluctuations of ions around dsDNAs. The introduction of flexibility of dsDNAs softens the vdW contact wall and induces more counterion fluctuations around dsDNAs. In addition, flexibility facilitates the Na+ ions dynamics affecting their distribution. The results quantify the extent of attraction influenced by dsDNA flexibility and further emphasize the importance of non-continuum solvation approaches. Full article
(This article belongs to the Special Issue Biophysics of Nucleic Acids Celebrating the 75th Birthday of Professor Kenneth J. Breslauer)
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Graphical abstract

21 pages, 7690 KiB  
Article
Thermodynamic Factors That Drive Sequence-Specific DNA Binding of Designed, Synthetic Minor Groove Binding Agents
by Ananya Paul, Abdelbasset A. Farahat, David W. Boykin and W. David Wilson
Life 2022, 12(5), 681; https://doi.org/10.3390/life12050681 - 4 May 2022
Cited by 5 | Viewed by 2348
Abstract
Ken Breslauer began studies on the thermodynamics of small cationic molecules binding in the DNA minor groove over 30 years ago, and the studies reported here are an extension of those ground-breaking reports. The goals of this report are to develop a detailed [...] Read more.
Ken Breslauer began studies on the thermodynamics of small cationic molecules binding in the DNA minor groove over 30 years ago, and the studies reported here are an extension of those ground-breaking reports. The goals of this report are to develop a detailed understanding of the binding thermodynamics of pyridine-based sequence-specific minor groove binders that have different terminal cationic groups. We apply biosensor-surface plasmon resonance and ITC methods to extend the understanding of minor groove binders in two directions: (i) by using designed, heterocyclic dicationic minor groove binders that can incorporate a G•C base pair (bp), with flanking AT base pairs, into their DNA recognition site, and bind to DNA sequences specifically; and (ii) by using a range of flanking AT sequences to better define molecular recognition of the minor groove. A G•C bp in the DNA recognition site causes a generally more negative binding enthalpy than with most previously used pure AT binding sites. The binding is enthalpy-driven at 25 °C and above. The flanking AT sequences also have a large effect on the binding energetics with the -AAAGTTT- site having the strongest affinity. As a result of these studies, we now have a much better understanding of the effects of the DNA sequence and compound structure on the molecular recognition and thermodynamics of minor groove complexes. Full article
(This article belongs to the Special Issue Biophysics of Nucleic Acids Celebrating the 75th Birthday of Professor Kenneth J. Breslauer)
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9 pages, 1522 KiB  
Article
Structural Responses of Nucleic Acids to Mars-Relevant Salts at Deep Subsurface Conditions
by Jim-Marcel Knop, Sanjib K. Mukherjee, Stewart Gault, Charles S. Cockell and Roland Winter
Life 2022, 12(5), 677; https://doi.org/10.3390/life12050677 - 2 May 2022
Cited by 5 | Viewed by 1851
Abstract
High pressure deep subsurface environments of Mars may harbor high concentrations of dissolved salts, such as perchlorates, yet we know little about how these salts influence the conditions for life, particularly in combination with high hydrostatic pressure. We investigated the effects of high [...] Read more.
High pressure deep subsurface environments of Mars may harbor high concentrations of dissolved salts, such as perchlorates, yet we know little about how these salts influence the conditions for life, particularly in combination with high hydrostatic pressure. We investigated the effects of high magnesium perchlorate concentrations compared to sodium and magnesium chloride salts and high pressure on the conformational dynamics and stability of double-stranded B-DNA and, as a representative of a non-canonical DNA structure, a DNA-hairpin (HP), whose structure is known to be rather pressure-sensitive. To this end, fluorescence spectroscopies including single-molecule FRET methodology were applied. Our results show that the stability both of the B-DNA as well as the DNA-HP is largely preserved at high pressures and high salt concentrations, including the presence of chaotropic perchlorates. The perchlorate anion has a small destabilizing effect compared to chloride, however. These results show that high pressures at the kbar level and perchlorate anions can modify the stability of nucleic acids, but that they do not represent a barrier to the gross stability of such molecules in conditions associated with the deep subsurface of Mars. Full article
(This article belongs to the Special Issue Biophysics of Nucleic Acids Celebrating the 75th Birthday of Professor Kenneth J. Breslauer)
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Graphical abstract

12 pages, 1328 KiB  
Article
Self-Consistent Parameterization of DNA Residues for the Non-Polarizable AMBER Force Fields
by Amelia L. Schneider, Amanda V. Albrecht, Kenneth Huang, Markus W. Germann and Gregory M. K. Poon
Life 2022, 12(5), 666; https://doi.org/10.3390/life12050666 - 30 Apr 2022
Viewed by 2413
Abstract
Fixed-charge (non-polarizable) forcefields are accurate and computationally efficient tools for modeling the molecular dynamics of nucleic acid polymers, particularly DNA, well into the µs timescale. The continued utility of these forcefields depends in part on expanding the residue set in step with advancing [...] Read more.
Fixed-charge (non-polarizable) forcefields are accurate and computationally efficient tools for modeling the molecular dynamics of nucleic acid polymers, particularly DNA, well into the µs timescale. The continued utility of these forcefields depends in part on expanding the residue set in step with advancing nucleic acid chemistry and biology. A key step in parameterizing new residues is charge derivation which is self-consistent with the existing residues. As atomic charges are derived by fitting against molecular electrostatic potentials, appropriate structural models are critical. Benchmarking against the existing charge set used in current AMBER nucleic acid forcefields, we report that quantum mechanical models of deoxynucleosides, even at a high level of theory, are not optimal structures for charge derivation. Instead, structures from molecular mechanics minimization yield charges with up to 6-fold lower RMS deviation from the published values, due to the choice of such an approach in the derivation of the original charge set. We present a contemporary protocol for rendering self-consistent charges as well as optimized charges for a panel of nine non-canonical residues that will permit comparison with literature as well as studying the dynamics of novel DNA polymers. Full article
(This article belongs to the Special Issue Biophysics of Nucleic Acids Celebrating the 75th Birthday of Professor Kenneth J. Breslauer)
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14 pages, 6196 KiB  
Article
Stabilization of G-Quadruplex-Duplex Hybrid Structures Induced by Minor Groove-Binding Drugs
by Lily Scott and Tigran V. Chalikian
Life 2022, 12(4), 597; https://doi.org/10.3390/life12040597 - 18 Apr 2022
Cited by 5 | Viewed by 2600
Abstract
Once it had been realized that G-quadruplexes exist in the cell and are involved in regulation of genomic processes, the quest for ligands recognizing these noncanonical structures was underway. Many organic compounds that tightly associate with G-quadruplexes have been identified. However, the specificity [...] Read more.
Once it had been realized that G-quadruplexes exist in the cell and are involved in regulation of genomic processes, the quest for ligands recognizing these noncanonical structures was underway. Many organic compounds that tightly associate with G-quadruplexes have been identified. However, the specificity of G-quadruplex-binding ligands towards individual structures remains problematic, as the common recognition element of these ligands is the G-tetrad. In this paper, we focus on G-quadruplex-duplex hybrids (QDH) containing a hairpin duplex incorporated as a stem-loop into the G-quadruplex core. The presence of a stem-loop renders QDH amenable to sequence-specific recognition by duplex-binding drugs. Should the thermodynamic crosstalk between the stem-loop and the tetraplex core be sufficiently strong, the drug binding to the loop would lead to the stabilization of the entire structure. We studied the stabilizing influence of the minor groove-binders netropsin and Hoechst 33258 on a family of QDH structures, as well as a G-quadruplex and a hairpin modeling the G-quadruplex core and the stem-loop of the QDH’s. We found that the binding of either drug results in an enhancement of the thermal stability of all DNA structures, as expressed by increases in the melting temperature, TM. Analysis of the hierarchical order of increases in TM revealed that the drug-induced stabilization arises from drug binding to the G-quadruplex domain of a QDH and the stem-loop, if the latter contains an all-AT binding site. This result attests to the thermodynamic crosstalk between the stem-loop and the tetraplex core of a QDH. Given the existing library of minor groove-binding drugs recognizing mixed A·T and G·C DNA sequences, our results point to an untapped avenue for sequence-specific recognition of QDH structures in vitro and, possibly, in vivo; thereby, opening the way for selective stabilization of four-stranded DNA structures at predetermined genomic loci, with implications for the control of genomic events. Full article
(This article belongs to the Special Issue Biophysics of Nucleic Acids Celebrating the 75th Birthday of Professor Kenneth J. Breslauer)
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11 pages, 1802 KiB  
Article
Replication Control of Human Telomere G-Quadruplex DNA by G-Quadruplex Ligands Dependent on Solution Environment
by Shuntaro Takahashi, Sudipta Bhowmik, Shinobu Sato, Shigeori Takenaka and Naoki Sugimoto
Life 2022, 12(4), 553; https://doi.org/10.3390/life12040553 - 7 Apr 2022
Cited by 4 | Viewed by 2276
Abstract
The human telomere region is known to contain guanine-rich repeats and form a guanine-quadruplex (G4) structure. As telomeres play a role in the regulation of cancer progression, ligands that specifically bind and stabilize G4 have potential therapeutic applications. However, as the human telomere [...] Read more.
The human telomere region is known to contain guanine-rich repeats and form a guanine-quadruplex (G4) structure. As telomeres play a role in the regulation of cancer progression, ligands that specifically bind and stabilize G4 have potential therapeutic applications. However, as the human telomere sequence can form G4 with various topologies due to direct interaction by ligands and indirect interaction by the solution environment, it is of great interest to study the topology-dependent control of replication by ligands. In the present study, a DNA replication assay of a template with a human telomere G4 sequence in the presence of various ligands was performed. Cyclic naphthalene diimides (cNDI1 and cNDI2) efficiently increased the replication stall of the template DNA at G4 with an anti-parallel topology. This inhibition was stability-dependent and topology-selective, as the replication of templates with hybrid or parallel G4 structures was not affected by the cNDI and cNDI2. Moreover, the G4 ligand fisetin repressed replication with selectivity for anti-parallel and hybrid G4 structures without stabilization. Finally, the method used, referred to as quantitative study of topology-dependent replication (QSTR), was adopted to evaluate the correlation between the replication kinetics and the stability of G4. Compared to previous results obtained using a modified human telomere sequence, the relationship between the stability of G4 and the effect on the topology-dependent replication varied. Our results suggest that native human telomere G4 is more flexible than the modified sequence for interacting with ligands. These findings indicate that the modification of the human telomeric sequence forces G4 to rigidly form a specific structure of G4, which can restrict the change in topology-dependent replication by some ligands. Full article
(This article belongs to the Special Issue Biophysics of Nucleic Acids Celebrating the 75th Birthday of Professor Kenneth J. Breslauer)
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Review

Jump to: Editorial, Research

42 pages, 7386 KiB  
Review
Forces Driving a Magic Bullet to Its Target: Revisiting the Role of Thermodynamics in Drug Design, Development, and Optimization
by Conceição A. Minetti and David P. Remeta
Life 2022, 12(9), 1438; https://doi.org/10.3390/life12091438 - 15 Sep 2022
Cited by 5 | Viewed by 3554
Abstract
Drug discovery strategies have advanced significantly towards prioritizing target selectivity to achieve the longstanding goal of identifying “magic bullets” amongst thousands of chemical molecules screened for therapeutic efficacy. A myriad of emerging and existing health threats, including the SARS-CoV-2 pandemic, alarming increase in [...] Read more.
Drug discovery strategies have advanced significantly towards prioritizing target selectivity to achieve the longstanding goal of identifying “magic bullets” amongst thousands of chemical molecules screened for therapeutic efficacy. A myriad of emerging and existing health threats, including the SARS-CoV-2 pandemic, alarming increase in bacterial resistance, and potentially fatal chronic ailments, such as cancer, cardiovascular disease, and neurodegeneration, have incentivized the discovery of novel therapeutics in treatment regimens. The design, development, and optimization of lead compounds represent an arduous and time-consuming process that necessitates the assessment of specific criteria and metrics derived via multidisciplinary approaches incorporating functional, structural, and energetic properties. The present review focuses on specific methodologies and technologies aimed at advancing drug development with particular emphasis on the role of thermodynamics in elucidating the underlying forces governing ligand–target interaction selectivity and specificity. In the pursuit of novel therapeutics, isothermal titration calorimetry (ITC) has been utilized extensively over the past two decades to bolster drug discovery efforts, yielding information-rich thermodynamic binding signatures. A wealth of studies recognizes the need for mining thermodynamic databases to critically examine and evaluate prospective drug candidates on the basis of available metrics. The ultimate power and utility of thermodynamics within drug discovery strategies reside in the characterization and comparison of intrinsic binding signatures that facilitate the elucidation of structural–energetic correlations which assist in lead compound identification and optimization to improve overall therapeutic efficacy. Full article
(This article belongs to the Special Issue Biophysics of Nucleic Acids Celebrating the 75th Birthday of Professor Kenneth J. Breslauer)
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Graphical abstract

16 pages, 3406 KiB  
Review
Nucleic Acid Thermodynamics Derived from Mechanical Unzipping Experiments
by Paolo Rissone and Felix Ritort
Life 2022, 12(7), 1089; https://doi.org/10.3390/life12071089 - 20 Jul 2022
Cited by 5 | Viewed by 2688
Abstract
Force-spectroscopy techniques have led to significant progress in studying the physicochemical properties of biomolecules that are not accessible in bulk assays. The application of piconewton forces with laser optical tweezers to single nucleic acids has permitted the characterization of molecular thermodynamics and kinetics [...] Read more.
Force-spectroscopy techniques have led to significant progress in studying the physicochemical properties of biomolecules that are not accessible in bulk assays. The application of piconewton forces with laser optical tweezers to single nucleic acids has permitted the characterization of molecular thermodynamics and kinetics with unprecedented accuracy. Some examples are the hybridization reaction between complementary strands in DNA and the folding of secondary, tertiary, and other heterogeneous structures, such as intermediate and misfolded states in RNA. Here we review the results obtained in our lab on deriving the nearest-neighbor free energy parameters in DNA and RNA duplexes from mechanical unzipping experiments. Remarkable nonequilibrium effects are also observed, such as the large irreversibility of RNA unzipping and the formation of non-specific secondary structures in single-stranded DNA. These features originate from forming stem-loop structures along the single strands of the nucleic acid. The recently introduced barrier energy landscape model quantifies kinetic trapping effects due to stem-loops being applicable to both RNA and DNA. The barrier energy landscape model contains the essential features to explain the many behaviors observed in heterogeneous nucleic-acid folding. Full article
(This article belongs to the Special Issue Biophysics of Nucleic Acids Celebrating the 75th Birthday of Professor Kenneth J. Breslauer)
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10 pages, 2697 KiB  
Review
Metal Ion-Directed Specific DNA Structures and Their Functions
by Toshihiro Ihara, Yusuke Kitamura and Yousuke Katsuda
Life 2022, 12(5), 686; https://doi.org/10.3390/life12050686 - 5 May 2022
Cited by 3 | Viewed by 2557
Abstract
Various DNA structures, including specific metal ion complexes, have been designed based on the knowledge of canonical base pairing as well as general coordination chemistry. The role of metal ions in these studies is quite broad and diverse. Metal ions can be targets [...] Read more.
Various DNA structures, including specific metal ion complexes, have been designed based on the knowledge of canonical base pairing as well as general coordination chemistry. The role of metal ions in these studies is quite broad and diverse. Metal ions can be targets themselves in analytical applications, essential building blocks of certain DNA structures that one wishes to construct, or they can be responsible for signal generation, such as luminescence or redox. Using DNA conjugates with metal chelators, one can more freely design DNA complexes with diverse structures and functions by following the simple HSAB rule. In this short review, the authors summarize a part of their DNA chemistries involving specific metal ion coordination. It consists of three topics: (1) significant stabilization of DNA triple helix by silver ion; (2) metal ion-directed dynamic sequence edition through global conformational change by intramolecular complexation; and (3) reconstruction of luminescent lanthanide complexes on DNA and their analytical applications. Full article
(This article belongs to the Special Issue Biophysics of Nucleic Acids Celebrating the 75th Birthday of Professor Kenneth J. Breslauer)
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13 pages, 3463 KiB  
Review
Developing Community Resources for Nucleic Acid Structures
by Helen M. Berman, Catherine L. Lawson and Bohdan Schneider
Life 2022, 12(4), 540; https://doi.org/10.3390/life12040540 - 6 Apr 2022
Cited by 10 | Viewed by 5397
Abstract
In this review, we describe the creation of the Nucleic Acid Database (NDB) at Rutgers University and how it became a testbed for the current infrastructure of the RCSB Protein Data Bank. We describe some of the special features of the NDB and [...] Read more.
In this review, we describe the creation of the Nucleic Acid Database (NDB) at Rutgers University and how it became a testbed for the current infrastructure of the RCSB Protein Data Bank. We describe some of the special features of the NDB and how it has been used to enable research. Plans for the next phase as the Nucleic Acid Knowledgebase (NAKB) are summarized. Full article
(This article belongs to the Special Issue Biophysics of Nucleic Acids Celebrating the 75th Birthday of Professor Kenneth J. Breslauer)
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