A Rapid Computational Screening of Millions of Molecules to Identify Sequence-Specific DNA Minor Groove Binders via Physicochemical Descriptors

Pant, Pawan Kumar; Jayaram, B.

doi:10.1007/7355_2021_122

Cited by 5 publications

(2 citation statements)

References 76 publications

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“…All the modified nucleic acid–p19 complexes (along with the control/reference complex) were simulated using all-atom explicit-solvent molecular dynamics (MD) simulations (400 ns, 3 replicates each) followed by structure, dynamic, and energetic analysis. MD simulations are a powerful tool for providing insights into the structure, function, and dynamics of biomolecules at the molecular level. − In recent years, MD simulations have been thoroughly utilized to predict the stability, conformational changes, and dynamics of nucleic acids/modified nucleic acids and their interactions with other biological systems. − Strikingly, we noticed that a few modified nucleic acid molecules designed in this study retained double-helical structural integrity and displayed enhanced p19 binding. Such molecules can preferentially interact with the viral p19 protein, resulting in the availability of the plant siRNA for RISC formation, leading to viral mRNA degradation.…”

Section: Introductionmentioning

confidence: 81%

Probing the Nucleic Acid Flexibility to Disarm the Viral Counter-Defense Machinery: Design and Characterization of Potent p19 Inhibitors

Pant,

Leese

2023

J. Phys. Chem. B

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Plant viruses are highly destructive and significant contributors to several global pandemics and epidemics in plants. A viral disease outbreak in plants can cause a scarcity of food supply and is a severe concern to humanity. The siRNA (small interfering RNA)-mediated RNA-induced silencing complex (RISC) formation is a primary defense mechanism in plants against viruses, where the RISC binds and degrades viral mRNAs. As a counter-defense, many viruses encode RNA-silencing suppressor proteins (e.g., the p19 protein from the Tombusviridae family) for viral proliferation in plants. The functional form of p19 (homodimer) binds to plant siRNA with high affinities, thereby interrupting the RISC formation and thus preventing the viral mRNA silencing in plants. By altering the RISC formation, the p19 protein helps the virus invasion in the plant and ultimately stunts host growth. In this study, we designed several modified siRNA-based molecules for p19 inhibition. The viral p19 protein is known to interact predominantly through H-bonds with 2′-OH and phosphates of the plant siRNA. We utilized this information and in silico-designed flexible substituents of siRNA, where we removed the C2′−C3′ bond in each nucleotide unit. We performed all-atom explicit-solvent molecular dynamics simulations (400 ns, 3 replicates each) for control/modified siRNA�p19 complexes (8 in total) followed by energetic estimations. Strikingly, in a few modified complexes, the siRNA not only retained the double-helical structural integrity but also displayed remarkably enhanced p19 binding compared to the control siRNA; hence, we consider it important to perform biological and chemical in vitro and in vivo studies on proposed flexible nucleic acids as p19 inhibitors for crop protection.

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Section: Introductionmentioning

confidence: 81%

Probing the Nucleic Acid Flexibility to Disarm the Viral Counter-Defense Machinery: Design and Characterization of Potent p19 Inhibitors

Pant,

Leese

2023

J. Phys. Chem. B

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“…The existence of the Z-form in the processes of gene expression as well as regulation along with cancer and autoimmune conditions has already been established with experimental studies. − We believe that the robustness of the designed Z-DNA molecule could help in understanding the role of Z-DNA form in biological processes. Further, several modified nucleosides have emerged as potent drug candidates. − Due to the strong binding of modified ssDNA to modified ssDNA in the model ZDNA structure, it would be interesting to examine the role of such oligonucleotides in anticancer therapy (as AOs). Moreover, with the high stability of the model ZDNA, even in salt-deprived conditions, the use of such molecules as a robust construction material in DNA origami is foreseen.…”

Section: Discussionmentioning

confidence: 99%

Harmonizing Interstrand Electrostatic Repulsion by Conformational Rigidity in Counterion-Deprived Z-DNA: A Molecular Dynamics Study

Sharma

2022

J. Phys. Chem. B

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Deoxyribonucleic acid (DNA) is a vital biomacromolecule. Although the right-handed B-DNA type helical structure is the most abundant and extensively studied form of DNA, several noncanonical forms, such as triplex, quadruplex, Z-DNA, A-DNA, and ss-DNA, have been probed from time to time to gain insights into the DNA's function. Z-DNA was recently found to be involved in cancer and several autoimmune diseases. In the present Article, we evaluated the conformational stability of locked-sugar-based Z-DNA via all-atom explicit-solvent molecular dynamics simulations and found that the modified DNA maintained the left-handed conformation even in the absence of counterions, wherein the structural rigidity dominates over the electrostatic repulsion between the complementary strands. The control Z-DNA without counterions, as expected, instantaneously resulted in unfolded states. The remarkable stability of the conformationally locked model system was thoroughly investigated via structural and energetic perspectives and was probably the result of the backbone widening in tandem with enhanced electrostatics between complementary strands. We believe that the design of the proposed modified Z-DNA construct could help understand the otherwise delicate Z-DNA conformation even in salt-deprived conditions. The design could also motivate the medicinal use of short segments of such modified nucleotides and could be utilized in more advanced modeling techniques, such as DNA origami which has gained popularity in recent years.

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Design and Characterization of Neutral Linker‐Based Bis‐Intercalator via Computer Simulations: Balancing DNA Binding and Cellular Uptake

Pant

2024

Chemistry & Biodiversity

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Bis‐intercalators play a significant role in altering the DNA structure, affecting its stability, and potentially influencing various cellular processes. These compounds have gained considerable attention in medicinal chemistry and biochemistry due to their potential applications in cancer therapy, where they may interfere with DNA replication and transcription, leading to anticancer effects. Traditionally, these molecules often possess a high positive charge to enhance their affinity for the negatively charged DNA. However, due to a high positive charge, their cellular uptake is compromised, along with their enhanced potential off‐target effects. In this study, we utilized bis‐intercalator TOTO and replaced the charged linker segment (propane‐1,3‐diammonium) with a neutral peroxodisulphuric acid linker. Using molecular modeling and computer simulations (500 ns, 3 replicas), we investigated the potential of the designed molecule as a bis‐intercalator and compared the properties with the control bis‐intercalator bound to DNA. We observed that the designed bis‐intercalator exhibited improved DNA binding (as assessed through MM‐PBSA and Delphi methods) and membrane translocation permeability. With an overall reduced charge, significantly less off‐target binding of the designed molecule is also anticipated. Consequently, bis‐intercalators based on peroxodisulphuric linkers can potentially target DNA effectively, and their role in the future design of bis‐intercalators is foreseen.

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A Rapid Computational Screening of Millions of Molecules to Identify Sequence-Specific DNA Minor Groove Binders via Physicochemical Descriptors

Cited by 5 publications

References 76 publications

Probing the Nucleic Acid Flexibility to Disarm the Viral Counter-Defense Machinery: Design and Characterization of Potent p19 Inhibitors

Probing the Nucleic Acid Flexibility to Disarm the Viral Counter-Defense Machinery: Design and Characterization of Potent p19 Inhibitors

Harmonizing Interstrand Electrostatic Repulsion by Conformational Rigidity in Counterion-Deprived Z-DNA: A Molecular Dynamics Study

Design and Characterization of Neutral Linker‐Based Bis‐Intercalator via Computer Simulations: Balancing DNA Binding and Cellular Uptake

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