scholarly journals Elucidation of an essential function of the unique charged domain of Plasmodium topoisomerase III

2020 ◽  
Vol 477 (24) ◽  
pp. 4745-4767
Author(s):  
Shephali Bansod ◽  
Navneet Bung ◽  
Priyanka Singh ◽  
Niranjan Suthram ◽  
Himashree Choudhury ◽  
...  
Keyword(s):  
Ectopic Expression ◽  
Stable State ◽  
Dynamics Simulation ◽  
Essential Requirement ◽  
Dna Structures ◽  
Recq Helicases ◽  
Catalytic Active Site ◽  
Topoisomerase Iii ◽  
Essential Function ◽  
Positively Charged

Topoisomerase III (TopoIII) along with RecQ helicases are required for the resolution of abnormal DNA structures that result from the stalling of replication forks. Sequence analyses have identified a putative TopoIII in the Plasmodium falciparum genome (PfTopoIII). PfTopoIII shows dual nuclear and mitochondrial localization. The expression and association of PfTopoIII with mtDNA are tightly linked to the asexual replication of the parasite. In this study, we observed that PfTopoIII physically interacts with PfBlm and PfWrn. Sequence alignment and domain analyses have revealed that it contains a unique positively charged region, spanning 85 amino acids, within domain II. A molecular dynamics simulation study revealed that this unstructured domain communicates with DNA and attains a thermodynamically stable state upon DNA binding. Here, we found that the association between PfTopoIII and the mitochondrial genome is negatively affected by the absence of the charged domain. Our study shows that PfTOPOIII can completely rescue the slow growth phenotype of the ΔtopoIII strain in Saccharomyces cerevisiae, but neither PfY421FtopoIII (catalytic-active site mutant) nor Pf(Δ259–337)topoIII (charged region deletion mutant) can functionally complement ScTOPOIII. Hydroxyurea (HU) led to stalling of the replication fork during the S phase, caused moderate toxicity to the growth of P. falciparum, and was associated with concomitant transcriptional up-regulation of PfTOPOIII. In addition, ectopic expression of PfTOPOIII reversed HU-induced toxicity. Interestingly, the expression of Pf(Δ259–337)topoIII failed to reverse HU-mediated toxicity. Taken together, our results establish the importance of TopoIII during Plasmodium replication and emphasize the essential requirement of the charged domain in PfTopoIII function.

Human RecQ helicases in transcription-associated stress management: bridging the gap between DNA and RNA metabolism

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Tulika Das ◽  
Surasree Pal ◽  
Agneyo Ganguly
Keyword(s):  
Genome Integrity ◽  
Complex Structures ◽  
Huge Number ◽  
Dna Helicases ◽  
Dna Structures ◽  
Recq Helicases ◽  
Dna And Rna ◽  
Cellular Dna ◽  
Almost All ◽  
Transcription And Replication

Abstract RecQ helicases are a highly conserved class of DNA helicases that play crucial role in almost all DNA metabolic processes including replication, repair and recombination. They are able to unwind a wide variety of complex intermediate DNA structures that may result from cellular DNA transactions and hence assist in maintaining genome integrity. Interestingly, a huge number of recent reports suggest that many of the RecQ family helicases are directly or indirectly involved in regulating transcription and gene expression. On one hand, they can remove complex structures like R-loops, G-quadruplexes or RNA:DNA hybrids formed at the intersection of transcription and replication. On the other hand, emerging evidence suggests that they can also regulate transcription by directly interacting with RNA polymerase or recruiting other protein factors that may regulate transcription. This review summarizes the up to date knowledge on the involvement of three human RecQ family proteins BLM, WRN and RECQL5 in transcription regulation and management of transcription associated stress.

scholarly journals Non-B DNA Secondary Structures and Their Resolution by RecQ Helicases

2011 ◽  
Vol 2011 ◽  
pp. 1-15 ◽  
Author(s):  
Sudha Sharma
Keyword(s):  
Transcriptional Control ◽  
Molecular Targets ◽  
Secondary Structures ◽  
Special Focus ◽  
Dna Helicases ◽  
Dna Structures ◽  
Recq Helicases ◽  
Alternative Structures ◽  
Dna Secondary Structures ◽  
Secondary Dna Structures

In addition to the canonical B-form structure first described by Watson and Crick, DNA can adopt a number of alternative structures. These non-B-form DNA secondary structures form spontaneously on tracts of repeat sequences that are abundant in genomes. In addition, structured forms of DNA with intrastrand pairing may arise on single-stranded DNA produced transiently during various cellular processes. Such secondary structures have a range of biological functions but also induce genetic instability. Increasing evidence suggests that genomic instabilities induced by non-B DNA secondary structures result in predisposition to diseases. Secondary DNA structures also represent a new class of molecular targets for DNA-interactive compounds that might be useful for targeting telomeres and transcriptional control. The equilibrium between the duplex DNA and formation of multistranded non-B-form structures is partly dependent upon the helicases that unwind (resolve) these alternate DNA structures. With special focus on tetraplex, triplex, and cruciform, this paper summarizes the incidence of non-B DNA structures and their association with genomic instability and emphasizes the roles of RecQ-like DNA helicases in genome maintenance by resolution of DNA secondary structures. In future, RecQ helicases are anticipated to be additional molecular targets for cancer chemotherapeutics.

scholarly journals Uncovering an allosteric mode of action for a selective inhibitor of human Bloom syndrome protein

2020 ◽  
Author(s):  
X. Chen ◽  
Y. Ali ◽  
C.E.L. Fisher ◽  
R. Arribas-Bosacoma ◽  
M.B. Rajasekaran ◽  
...  
Keyword(s):  
Synthetic Lethality ◽  
Specific Inhibitor ◽  
Bloom Syndrome ◽  
Dna Helicase ◽  
Holliday Junctions ◽  
Dna Structures ◽  
Recq Helicases ◽  
Promising Target ◽  
Opening And Closing ◽  
Syndrome Protein

ABSTRACTBLM (Bloom syndrome protein) is a RECQ-family helicase involved in the dissolution of complex DNA structures and repair intermediates. Synthetic lethality analysis implicates BLM as a promising target in a range of cancers with defects in the DNA damage response, however selective small molecule inhibitors of defined mechanism are currently lacking. Here we identify and characterise a specific inhibitor of BLM’s ATPase-coupled DNA helicase activity, by allosteric trapping of a DNA-bound translocation intermediate. Crystallographic structures of BLM-DNA-ADP-inhibitor complexes identify a hitherto unknown interdomain interface, whose opening and closing are integral to translocation of ssDNA, and which provides a highly selective pocket for drug discovery. Comparison with structures of other RECQ helicases provides a model for branch migration of Holliday junctions by BLM.

scholarly journals Computational Analysis for Physicochemical Properties of Compounds in Senna auriculata Leaves Methanolic Extract to have Antidiabetic Potentials and their Molecular Interaction with α-amylase

2021 ◽  
pp. 30-42
Author(s):  
Abdulaziz Bin Dukhyil
Keyword(s):  
Molecular Docking ◽  
Physicochemical Properties ◽  
Methanolic Extract ◽  
Natural Compounds ◽  
Physicochemical Analysis ◽  
Dynamics Simulation ◽  
Carbohydrate Hydrolysis ◽  
Catalytic Active Site ◽  
Inhibitory Potential

Aims: Diabetes mellitus (DM) is chronic disorder well known for increased glucose level in blood. This disease can be controlled by inhibiting the enzyme (e.g., α-amylase) involve in carbohydrate hydrolysis. Senna auriculata leaves methanolic extract (SALME) have potential antidiabetic properties and it was also found to be safe in preclinical studies. In this study the aim was to explore the molecular interactions of α-amylase and bioactive compounds in SALME and their physicochemical properties. Methodology: Computational approach such as molecular docking and physicochemical analysis prediction was applied to understand the antidiabetic potential of natural compounds present in SALME. Results: The results showed from physicochemical analysis that out of 11 only 7 compounds are having drug like properties which are orally and intestinally better bioavailable. Furthermore, molecular docking analysis explained that three compounds (C3, C4, and C7) have lower binding energy, ΔG (-8, -9.1, -9.5 kcal/mol) and better binding affinity, Ki (7.31 x 105, 4.68 x 106, and 9.2 x 106 M-1, respectively) than the acarbose ΔG (-7.8 kcal/mol) and Ki (6.18 x 105 M-1), a well-known FDA approved medication for DM. The study also explained the binding pattern that the catalytic residue such as Asp197, Glu233 and Asp300 are involved in stabilizing the natural compounds with in the catalytic active site of target enzyme. Conclusions: From the results it has been concluded that these three compounds found in SALME have better inhibitory potential for α-amylase in comparison with acarbose. Further validation of the findings is required through molecular dynamics simulation, ADME-T study, and in-vitro enzyme inhibition by the purified compounds.

Influence of the size and charge of gold nanoclusters on complexation with siRNA: a molecular dynamics simulation study

2015 ◽  
Vol 17 (45) ◽  
pp. 30307-30317 ◽  
Author(s):  
Sathish Kumar Mudedla ◽  
Ettayapuram Ramaprasad Azhagiya Singam ◽  
Kanagasabai Balamurugan ◽  
Venkatesan Subramanian
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Molecular Dynamics Simulations ◽  
Simulation Study ◽  
Gold Nanoclusters ◽  
Dynamics Simulation ◽  
Classical Molecular Dynamics ◽  
Dynamics Simulations ◽  
Positively Charged

The complexation of siRNA with positively charged gold nanoclusters has been studied using classical molecular dynamics simulations.

scholarly journals Discovery of New Selective Butyrylcholinesterase (BChE) Inhibitors with Anti-Aβ Aggregation Activity: Structure-Based Virtual Screening, Hit Optimization and Biological Evaluation

Molecules ◽  
2019 ◽  
Vol 24 (14) ◽  
pp. 2568 ◽  
Author(s):  
Cheng-Shi Jiang ◽  
Yong-Xi Ge ◽  
Zhi-Qiang Cheng ◽  
Yin-Yin Wang ◽  
Hong-Rui Tao ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Cell Model ◽  
Neuroblastoma Cells ◽  
Biological Evaluation ◽  
Dynamics Simulation ◽  
Dependent Manner ◽  
Binding Modes ◽  
Catalytic Active Site ◽  
Aggregation Activity

In this study, a series of selective butyrylcholinesterase (BChE) inhibitors was designed and synthesized from the structural optimization of hit 1, a 4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzoic acid derivative identified by virtual screening our compound library. The in vitro enzyme assay results showed that compounds 9 ((4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)phenyl)(pyrrolidin-1-yl)methanone) and 23 (N-(2-bromophenyl)-4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzamide) displayed improved BChE inhibitory activity and good selectivity towards BChE versus AChE. Their binding modes were probed by molecular docking and further validated by molecular dynamics simulation. Kinetic analysis together with molecular modeling studies suggested that these derivatives could target both the catalytic active site (CAS) and peripheral anionic site (PAS) of BChE. In addition, the selected compounds 9 and 23 displayed anti-Aβ1–42 aggregation activity in a dose-dependent manner, and they did not show obvious cytotoxicity towards SH-SY5Y neuroblastoma cells. Also, both compounds showed significantly protective activity against Aβ1-42-induced toxicity in a SH-SY5Y cell model. The present results provided a new valuable chemical template for the development of selective BChE inhibitors.

scholarly journals Exploring Aurone Derivatives as Potential Human Pancreatic Lipase Inhibitors through Molecular Docking and Molecular Dynamics Simulations

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4657
Author(s):  
Phuong Thuy Viet Nguyen ◽  
Han Ai Huynh ◽  
Dat Van Truong ◽  
Thanh-Dao Tran ◽  
Cam-Van Thi Vo
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Pancreatic Lipase ◽  
Inhibitory Activity ◽  
Dynamics Simulation ◽  
Stable Complex ◽  
Catalytic Active Site ◽  
Dynamics Simulations

Inhibition of human pancreatic lipase, a crucial enzyme in dietary fat digestion and absorption, is a potent therapeutic approach for obesity treatment. In this study, human pancreatic lipase inhibitory activity of aurone derivatives was explored by molecular modeling approaches. The target protein was human pancreatic lipase (PDB ID: 1LPB). The 3D structures of 82 published bioactive aurone derivatives were docked successfully into the protein catalytic active site, using AutoDock Vina 1.5.7.rc1. Of them, 62 compounds interacted with the key residues of catalytic trial Ser152-Asp176-His263. The top hit compound (A14), with a docking score of −10.6 kcal⋅mol−1, was subsequently submitted to molecular dynamics simulations, using GROMACS 2018.01. Molecular dynamics simulation results showed that A14 formed a stable complex with 1LPB protein via hydrogen bonds with important residues in regulating enzyme activity (Ser152 and Phe77). Compound A14 showed high potency for further studies, such as the synthesis, in vitro and in vivo tests for pancreatic lipase inhibitory activity.

Comparison of the effect of poly(N-vinyl caprolactam) and poly(N-isopropyl acrylamide) trimers on the stability of hydrated Na-montmorillonite: A molecular dynamics study

2020 ◽  
pp. 096739112093524
Author(s):  
Jiafang Xu ◽  
Moussa Camara ◽  
Hualin Liao ◽  
Hong Guo ◽  
Kouassi Louis Kra ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Stable State ◽  
Dynamics Simulation ◽  
Effect Of Temperature ◽  
Radius Of Gyration ◽  
Molecular Arrangement ◽  
Isopropyl Acrylamide ◽  
The Stability ◽  
The Impact

In the present study, we performed a molecular dynamics simulation of the intercalation of poly( N-isopropyl acrylamide) (NIPAM)3 and poly( N-vinyl caprolactam) (NVCL)3 trimers into Na-montmorillonite (Na-Mt) to evaluate their effects on the interlayer structure and the stability of hydrated Na-Mt. The impact of both trimers on the interlayer species and their dynamics properties at different temperatures in a canonical ensemble (NVT) were investigated. The results showed that the electrostatic forces exerted by Na cations on H2O molecules and the interlayer H2O molecular arrangement are not affected by the rise in temperature after adding both trimers. Trimer addition reinforced the structure of interlayer H2O molecules so that the effect of temperature increase on them became negligible. The structural dynamics evolution of the radius of gyration of both trimers showed the existence of conformation changes when temperature increased. These conformational changes are more complex in the case of (NVCL)3 than (NIPAM)3 due to its large monomers. Both trimers reduced the mobility of interlayer particles with a better inhibition effect obtained for (NVCL)3 compared to (NIPAM)3. The concentration profile of interlayers’ species showed the affinity of Na cations for clay mineral surfaces while H2O molecules moved away. Compared these two trimers, the most stable state of Na-Mt is achieved with (NVCL)3. These results could help highlight the inhibition properties of (NIPAM)3 and (NVCL)3 on hydrated Na-Mt and to predict its stability against changes in environmental conditions.

scholarly journals Molecular Dynamics Simulation of Nanoscale Elastic Properties of Hydrated Na-, Cs-, and Ca-Montmorillonite

2022 ◽  
Vol 12 (2) ◽  
pp. 678
Author(s):  
Lianfei Kuang ◽  
Qiyin Zhu ◽  
Xiangyu Shang ◽  
Xiaodong Zhao
Keyword(s):  
Molecular Dynamics ◽  
Water Content ◽  
Elastic Properties ◽  
Bonding Strength ◽  
Stable State ◽  
Dynamics Simulation ◽  
Basal Spacing ◽  
Stiffness Tensor ◽  
Interlayer Water ◽  
Out Of Plane

The knowledge of nanoscale mechanical properties of montmorillonite (MMT) with various compensation cations upon hydration is essential for many environmental engineering-related applications. This paper uses a Molecular Dynamics (MD) method to simulate nanoscale elastic properties of hydrated Na-, Cs-, and Ca-MMT with unconstrained system atoms. The variation of basal spacing of MMT shows step characteristics in the initial crystalline swelling stage followed by an approximately linear change in the subsequent osmotic swelling stage as the increasing of interlayer water content. The water content of MMT in the thermodynamic stable-state conditions during hydration is determined by comparing the immersion energy and hydration energy. Under this stable hydration state, the nanoscale elastic properties are further simulated by the constant strain method. Since the non-bonding strength between MMT lamellae is much lower than the boning strength within the mineral structure, the in-plane and out-of-plane strength of MMT has strong anisotropy. Simulated results including the stiffness tensor and linear elastic constants based on the assumption of orthotropic symmetry are all in good agreement with results from the literature. Furthermore, the out-of-plane stiffness tensor components of C33, C44, and C55 all fluctuate with the increase of interlayer water content, which is related to the formation of interlayer H-bonds and atom-free volume ratio. The in-plane stiffness tensor components C11, C22, and C12 decrease nonlinearly with the increase of water content, and these components are mainly controlled by the bonding strength of mineral atoms and the geometry of the hydrated MMT system. Young’s modulus in all three directions exhibits a nonlinear decrease with increasing water content.

scholarly journals Functional Differentiation of tbf1 Orthologues in Fission and Budding Yeasts

2008 ◽  
Vol 8 (2) ◽  
pp. 207-216 ◽  
Author(s):  
Moira M. Cockell ◽  
Libera Lo Presti ◽  
Lorenzo Cerutti ◽  
Elena Cano Del Rosario ◽  
Philippe M. Hauser ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Gene Family ◽  
Essential Gene ◽  
Pneumocystis Carinii ◽  
Ectopic Expression ◽  
Functional Differentiation ◽  
Regulation Of Transcription ◽  
Global Regulation ◽  
Telomere Function ◽  
Essential Function

ABSTRACT In Saccharomyces cerevisiae, TBF1, an essential gene, influences telomere function but also has other roles in the global regulation of transcription. We have identified a new member of the tbf1 gene family in the mammalian pathogen Pneumocystis carinii. We demonstrate by transspecies complementation that its ectopic expression can provide the essential functions of Schizosaccharomyces pombe tbf1 but that there is no rescue between fission and budding yeast orthologues. Our findings indicate that an essential function of this family of proteins has diverged in the budding and fission yeasts and suggest that effects on telomere length or structure are not the primary cause of inviability in S. pombe tbf1 null strains.

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