scholarly journals Forever Young: Structural Stability of Telomeric Guanine-Quadruplexes in Presence of Oxidative DNA Lesions

2020 ◽  
Author(s):  
Tom Miclot ◽  
Camille Corbier ◽  
Alessio Terenzi ◽  
Cécilia Hognon ◽  
Stéphanie Grandemange ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Dynamics ◽  
Structural Stability ◽  
Md Simulations ◽  
Dna Lesions ◽  
Computational Investigation ◽  
Telomeric Dna ◽  
G Quadruplex ◽  
The Stability

AbstractHuman telomeric DNA (h-Telo), in G-quadruplex (G4) conformation, is characterized by a remarkable structural stability that confers it the capacity to resist to oxidative stress producing one or even clustered 8-oxoguanine lesions. We present a combined experimental/computational investigation, by using circular dichroism in aqueous solutions, cellular immunofluorescence assays and molecular dynamics (MD) simulations, that identifies the crucial role of the stability of G4s to oxidative lesions, related also to their biological role as inhibitors of telomerase, an enzyme overexpressed in most cancers associated to oxidative stress.

Three Major Phosphoacceptor Sites in HIV-1 Capsid Protein Enhances its Structural Stability and Resistance Against the Inhibitor: Explication Through Molecular Dynamics Simulation, Molecular Docking and DFT Analysis

2020 ◽  
Vol 23 (1) ◽  
pp. 41-54 ◽  
Author(s):  
Nouman Rasool ◽  
Waqar Hussain
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Capsid Protein ◽  
Structural Stability ◽  
Md Simulations ◽  
Host Cells ◽  
Dynamics Simulation ◽  
Maximum Stability ◽  
The Stability ◽  
Hiv 1

Background: Human Immunodeficiency Virus 1 (HIV-1) is a lentivirus, which causes various HIV-associated infections. The HIV-1 core dissociation is essential for viral cDNA synthesis and phosphorylation of HIV-1 capsid protein (HIV-1 CA) plays an important role in it. Objective: The aim of this study was to explicate the role of three phosphoserine sites i.e. Ser109, Ser149 and Ser178 in the structural stability of HIV-1 CA, and it’s binding with GS-CA1, a novel potent inhibitor. Method: Eight complexes were analyzed and Molecular Dynamics (MD) simulations were performed to observe the stability of HIV-1 CA in the presence and absence of phosphorylation of serine residues at four different temperatures i.e. 300K, 325K, 340K and 350K, along with molecular docking and DFT analysis. Results: The structures showed maximum stability in the presence of phosphorylated serine residue. However, GS-CA1 docked most strongly with the native structure of HIV-1 CA i.e. binding affinity was -8.5 kcal/mol (Ki = 0.579 µM). Conclusion: These results suggest that the phosphorylation of these three serine residues weakens the binding of GS-CA1 with CA and casts derogatory effect on inhibition potential of this inhibitor, but it supports the stability of HIV-1 CA structure that can enhance regulation and replication of HIV-1 in host cells.

scholarly journals Molecular Dynamics Study of the Interaction of Carbon Nanotubes with Telomeric DNA Fragment Containing Noncanonical G-Quadruplex and i-Motif Forms

2020 ◽  
Vol 21 (6) ◽  
pp. 1925 ◽  
Author(s):  
Tomasz Panczyk ◽  
Patrycja Wojton ◽  
Pawel Wolski
Keyword(s):  
Carbon Nanotubes ◽  
Molecular Dynamics ◽  
Spatial Structure ◽  
Computational Procedure ◽  
Middle Part ◽  
Telomeric Dna ◽  
Neutral Ph ◽  
G Quadruplex ◽  
The Stability ◽  
Dynamics Simulations

This work deals with molecular dynamics simulations of systems composed of telomeric dsDNA fragments, iG, and functionalized carbon nanotubes, fCNT. The iG contains 90 nucleotides in total and in its middle part the noncanonical i-motif and G-quadruplex are formed. Two chiralities of the fCNT were used, i.e., (10,0) and (20,0) and these nanotubes were either on-tip functionalized by guanine containing functional groups or left without functionalization. We proposed a dedicated computational procedure, based on the replica exchange concept, for finding a thermodynamically optimal conformation of iG and fCNT without destroying the very fragile noncanonical parts of the iG. We found that iG forms a V-shape spatial structure with the noncanonical fragments located at the edge and the remaining dsDNA strands forming the arms of V letter. The optimal configuration of iG in reference to fCNT strongly depends on the on-tip functionalization of the fCNT. The carbon nanotube without functionalization moves freely between the dsDNA arms, while the presence of guanine residues leads to immobilization of the fCNT and preferential location of the nanotube tip near the junction between the dsDNA duplex and i-motif and G-quadruplex. We also studied how the presence of fCNT affects the stability of the i-motif at the neutral pH when the cytosine pairs are nonprotonated. We concluded that carbon nanotubes do not improve the stability of the spatial structure of i-motif also when it is a part of a bigger structure like the iG. Such an effect was described in literature in reference to carboxylated nanotubes. Our current results suggest that the stabilization of i-motif is most probably related to easy formation of semiprotonated cytosine pairs at neutral pH due to interaction with carboxylated carbon nanotubes.

scholarly journals Theoretical Study on the Photo-Oxidation and Photoreduction of an Azetidine Derivative as a Model of DNA Repair

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 2911
Author(s):  
Miriam Navarrete-Miguel ◽  
Antonio Francés-Monerris ◽  
Miguel A. Miranda ◽  
Virginie Lhiaubet-Vallet ◽  
Daniel Roca-Sanjuán
Keyword(s):  
Electron Transfer ◽  
Energy Barrier ◽  
Ring Opening ◽  
Dna Lesions ◽  
Barrier Heights ◽  
Dna Lesion ◽  
Electron Reduction ◽  
The Stability ◽  
Electron Transfer Processes

Photocycloreversion plays a central role in the study of the repair of DNA lesions, reverting them into the original pyrimidine nucleobases. Particularly, among the proposed mechanisms for the repair of DNA (6-4) photoproducts by photolyases, it has been suggested that it takes place through an intermediate characterized by a four-membered heterocyclic oxetane or azetidine ring, whose opening requires the reduction of the fused nucleobases. The specific role of this electron transfer step and its impact on the ring opening energetics remain to be understood. These processes are studied herein by means of quantum-chemical calculations on the two azetidine stereoisomers obtained from photocycloaddition between 6-azauracil and cyclohexene. First, we analyze the efficiency of the electron-transfer processes by computing the redox properties of the azetidine isomers as well as those of a series of aromatic photosensitizers acting as photoreductants and photo-oxidants. We find certain stereodifferentiation favoring oxidation of the cis-isomer, in agreement with previous experimental data. Second, we determine the reaction profiles of the ring-opening mechanism of the cationic, neutral, and anionic systems and assess their feasibility based on their energy barrier heights and the stability of the reactants and products. Results show that oxidation largely decreases the ring-opening energy barrier for both stereoisomers, even though the process is forecast as too slow to be competitive. Conversely, one-electron reduction dramatically facilitates the ring opening of the azetidine heterocycle. Considering the overall quantum-chemistry findings, N,N-dimethylaniline is proposed as an efficient photosensitizer to trigger the photoinduced cycloreversion of the DNA lesion model.

scholarly journals Structural genomics approach to investigate deleterious impact of nsSNPs in conserved telomere maintenance component 1

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Arunabh Choudhury ◽  
Taj Mohammad ◽  
Nikhil Samarth ◽  
Afzal Hussain ◽  
Md. Tabish Rehman ◽  
...  
Keyword(s):  
Noncovalent Interactions ◽  
Md Simulations ◽  
Telomere Maintenance ◽  
Nucleotide Polymorphisms ◽  
Telomeric Dna ◽  
Congenital Diseases ◽  
Ob Fold ◽  
Significant Conformational Change ◽  
The Stability ◽  
The Impact

AbstractConserved telomere maintenance component 1 (CTC1) is an important component of the CST (CTC1-STN1-TEN1) complex, involved in maintaining the stability of telomeric DNA. Several non-synonymous single-nucleotide polymorphisms (nsSNPs) in CTC1 have been reported to cause Coats plus syndrome and Dyskeratosis congenital diseases. Here, we have performed sequence and structure analyses of nsSNPs of CTC1 using state-of-the-art computational methods. The structure-based study focuses on the C-terminal OB-fold region of CTC1. There are 11 pathogenic mutations identified, and detailed structural analyses were performed. These mutations cause a significant disruption of noncovalent interactions, which may be a possible reason for CTC1 instability and consequent diseases. To see the impact of such mutations on the protein conformation, all-atom molecular dynamics (MD) simulations of CTC1-wild-type (WT) and two of the selected mutations, R806C and R806L for 200 ns, were carried out. A significant conformational change in the structure of the R806C mutant was observed. This study provides a valuable direction to understand the molecular basis of CTC1 dysfunction in disease progression, including Coats plus syndrome.

scholarly journals Structural Properties of G,T-Parallel Duplexes

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Anna Aviñó ◽  
Elena Cubero ◽  
Raimundo Gargallo ◽  
Carlos González ◽  
Modesto Orozco ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Structural Properties ◽  
Theoretical Calculations ◽  
Md Simulations ◽  
Theoretical Studies ◽  
Duplex Structure ◽  
Strong Stabilization ◽  
The Stability ◽  
The Impact

The structure of G,T-parallel-stranded duplexes of DNA carrying similar amounts of adenine and guanine residues is studied by means of molecular dynamics (MD) simulations and UV- and CD spectroscopies. In addition the impact of the substitution of adenine by 8-aminoadenine and guanine by 8-aminoguanine is analyzed. The presence of 8-aminoadenine and 8-aminoguanine stabilizes the parallel duplex structure. Binding of these oligonucleotides to their target polypyrimidine sequences to form the corresponding G,T-parallel triplex was not observed. Instead, when unmodified parallel-stranded duplexes were mixed with their polypyrimidine target, an interstrand Watson-Crick duplex was formed. As predicted by theoretical calculations parallel-stranded duplexes carrying 8-aminopurines did not bind to their target. The preference for the parallel-duplex over the Watson-Crick antiparallel duplex is attributed to the strong stabilization of the parallel duplex produced by the 8-aminopurines. Theoretical studies show that the isomorphism of the triads is crucial for the stability of the parallel triplex.

scholarly journals Telomeric G-Quadruplexes: From Human to Tetrahymena Repeats

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Erika Demkovičová ◽  
Ľuboš Bauer ◽  
Petra Krafčíková ◽  
Katarína Tlučková ◽  
Petra Tóthova ◽  
...  
Keyword(s):  
Life Cycle ◽  
Base Substitution ◽  
Telomeric Dna ◽  
Purine Base ◽  
Telomeric Sequences ◽  
G Quadruplex ◽  
The Stability ◽  
Scientific Value ◽  
The Relationship ◽  
Adenine Base

The human telomeric and protozoal telomeric sequences differ only in one purine base in their repeats; TTAGGG in telomeric sequences; and TTGGGG in protozoal sequences. In this study, the relationship between G-quadruplexes formed from these repeats and their derivatives is analyzed and compared. The human telomeric DNA sequence G3(T2AG3)3 and related sequences in which each adenine base has been systematically replaced by a guanine were investigated; the result is Tetrahymena repeats. The substitution does not affect the formation of G-quadruplexes but may cause differences in topology. The results also show that the stability of the substituted derivatives increased in sequences with greater number of substitutions. In addition, most of the sequences containing imperfections in repeats which were analyzed in this study also occur in human and Tetrahymena genomes. Generally, the presence of G-quadruplex structures in any organism is a source of limitations during the life cycle. Therefore, a fuller understanding of the influence of base substitution on the structural variability of G-quadruplexes would be of considerable scientific value.

scholarly journals Atomistic Analysis of ToxN and ToxI Complex Unbinding Mechanism

2018 ◽  
Vol 19 (11) ◽  
pp. 3524 ◽  
Author(s):  
Guodong Hu ◽  
Xiu Yu ◽  
Yunqiang Bian ◽  
Zanxia Cao ◽  
Shicai Xu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Noncoding Rna ◽  
Md Simulations ◽  
Normal Function ◽  
Toxin Complex ◽  
Potentials Of Mean Force ◽  
Protein Toxins ◽  
Function Relationship ◽  
The Stability ◽  
Smd Simulations

ToxIN is a triangular structure formed by three protein toxins (ToxNs) and three specific noncoding RNA antitoxins (ToxIs). To respond to stimuli, ToxI is preferentially degraded, releasing the ToxN. Thus, the dynamic character is essential in the normal function interactions between ToxN and ToxI. Here, equilibrated molecular dynamics (MD) simulations were performed to study the stability of ToxN and ToxI. The results indicate that ToxI adjusts the conformation of 3′ and 5′ termini to bind to ToxN. Steered molecular dynamics (SMD) simulations combined with the recently developed thermodynamic integration in 3nD (TI3nD) method were carried out to investigate ToxN unbinding from the ToxIN complex. The potentials of mean force (PMFs) and atomistic pictures suggest the unbinding mechanism as follows: (1) dissociation of the 5′ terminus from ToxN, (2) missing the interactions involved in the 3′ terminus of ToxI without three nucleotides (G31, A32, and A33), (3) starting to unfold for ToxI, (4) leaving the binding package of ToxN for three nucleotides of ToxI, (5) unfolding of ToxI. This work provides information on the structure-function relationship at the atomistic level, which is helpful for designing new potent antibacterial drugs in the future.

scholarly journals The role of the antioxidant: Selenopyran in the stability of the antioxidant system to toxic effect of cadmium chloride

2007 ◽  
Vol 23 (5-6-1) ◽  
pp. 181-191
Author(s):  
U. Kravchenko ◽  
G. Borjaev ◽  
M. Nevitov ◽  
A. Ostapchuk ◽  
E. Kistanova
Keyword(s):  
Oxidative Stress ◽  
Antioxidant System ◽  
Antioxidant Defense ◽  
Age Groups ◽  
Selenium Concentration ◽  
Antioxidant Defense System ◽  
The Stability ◽  
Gpx Activity ◽  
Preventive Role

The purpose of the present work was, under conditions of the model experiment on rats, to tap the information about the features of shortterm acclimatization of the antioxidant system in various organs to toxicity of cadmium at stages of an ontogenesis and about the preventive role of the antioxidant selenopyran in this process. The obtained results showed the ontogenetic differences in the adaptive reactivity of the enzymatic antioxidant defense system in the most important organs and tissues of rats under conditions of oxidative stress induced by cadmium. The ontogenetic differences of Se redistribution in a body under influence of cadmium administration were found. The discovered decrease of Se concentration in the liver of young animals and the increase of its concentration in the liver of old animals correlated positively with the changes of GPx activity. Preventive administration of selenopyran (9- phenyl-simmetrical octa-hydroselenoxanthene) to old animals reduced the oxidative stress intensity. Animals of all age groups showed higher selenium concentration in the tissues and the increase in the selenium-dependent GPx activity.

scholarly journals Simulating Absorption Spectra of Flavonoids in Aqueous Solution: A Polarizable QM/MM Study

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 5853
Author(s):  
Sulejman Skoko ◽  
Matteo Ambrosetti ◽  
Tommaso Giovannini ◽  
Chiara Cappelli
Keyword(s):  
Molecular Dynamics ◽  
Aqueous Solution ◽  
Hydrogen Bonding ◽  
Force Field ◽  
Absorption Spectra ◽  
Computational Study ◽  
Md Simulations ◽  
Quantum Mechanical ◽  
Hydrogen Bonding Interactions

We present a detailed computational study of the UV/Vis spectra of four relevant flavonoids in aqueous solution, namely luteolin, kaempferol, quercetin, and myricetin. The absorption spectra are simulated by exploiting a fully polarizable quantum mechanical (QM)/molecular mechanics (MM) model, based on the fluctuating charge (FQ) force field. Such a model is coupled with configurational sampling obtained by performing classical molecular dynamics (MD) simulations. The calculated QM/FQ spectra are compared with the experiments. We show that an accurate reproduction of the UV/Vis spectra of the selected flavonoids can be obtained by appropriately taking into account the role of configurational sampling, polarization, and hydrogen bonding interactions.

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