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Computational study of μ-opioid receptor embedded in a realistic membrane 44

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Computational study of μ-opioid receptor embedded in a real...

44th Vietnam Conference on Theoretical Physics, VCTP 2019

作者： Tran, Thanh K. Nguyen, Toan T. Key Laboratory for Multiscale of Complex Systems VNU University of Science Vietnam National University 334 Nguyen Trai street Thanh Xuan district Hanoi120000 Viet Nam

Opioids are highly effective analgesics used to alleviate acute, surgical and cancer pains. However, utilization of opioids leads to adverse effects such as nausea, constipation, dizziness, somnolence, vomiting, especially, high addictive liability and drug-induced respiration depression. Ongoing efforts to generate safer opioid analgesics, such as designing biased agonist, peripheral opioids or endogenous opioid analogues, requires thorough understanding of the relationship between structure and function of the main target of opioids - μORs. In this research, the structural and dynamic of a μOR molecule embedded in membrane are studied by molecular dynamics simulation. Our results revealed the influences of disulfide linkage between CYS142-CYS219 and the transmembrane proline and glycine on μOR's dynamics and structure, as well as, their important role in μOR's functions. © 2020 IOP Publishing Ltd. All rights reserved.

关键词： Sulfur compounds

Evaluation of Colchicine's interaction with the ATP-binding region of mice NLRP3-NACHT domain using molecular docking and dynamics simulation 46

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Evaluation of Colchicine's interaction with the ATP-binding ...

46th Vietnam Conference on Theoretical Physics, VCTP 2021

作者： Lai, Hien T. T. Do, Ha M. Nguyen, Toan T. Key Laboratory for Multiscale Simulation of Complex Systems Department of Theoretical Physics Faculty of Physics VNU University of Science Vietnam National University Ͽ Hanoi 334 Nguyen Trai street Thanh Xuan district Hanoi Viet Nam The Key Laboratory of Enzyme and Protein Technology VNU University of Science Vietnam National University Ͽ Hanoi 334 Nguyen Trai street Thanh Xuan district Hanoi Viet Nam

Since the discovery of the role of NLRP3 in microbial infection in 2001, many studies have shown that NLRP3 play a key role in causing many mammal acute and chronic diseases. However, a full understanding of the mechanism of NLRP3 activation is still lacking. Our previous theoretical work and experimental evidence show the role of ATP in interacting with and activating the NATCH region of NLRP3. In this study, we continue to use bioinformatics and molecular dynamic (MD) simulation to evaluate the competitive impact of the interaction the ligand ATP and colchicine (COL) with this NACHT protein. The later ligand is a medication to treat gout attacks. Our results show that COL bind stably to the ATP binding pocket of mice NACHT domain with high numbers of hydrophobic and van der Waals interactions, while hydrogen bond and electrostatic interactions are important types of contact for keeping ATP at its NACHT pocket. Our results assist in building in-silico screening model for natural compounds with pharmacological effects to NLRP3 similar to colchicine with few side effects. In addition, this work helps to better understand the balance between this inflammasome activation and inhibition, which will help in the improvement and development of new therapies for related diseases. © Published under licence by IOP Publishing Ltd.

关键词： Chemical activation

Investigation of Allopurinol binding mechanism to allele HLA-A∗33:03 by using Molecular Dynamics simulation 46

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Investigation of Allopurinol binding mechanism to allele HLA...

46th Vietnam Conference on Theoretical Physics, VCTP 2021

作者： Pham, Oanh P. Lai, Hien T.T. Tran, Duong B. Le, Linh T. P. Nguyen, Anh Thi Van Nguyen, Hang Thi Thu Nguyen, Toan T. Key Laboratory for Multiscale Simulation of Complex Systems VNU University of Science Vietnam National University 334 Nguyen Trai Street Thanh Xuan Dist Hanoi120000 Viet Nam Key Laboratory of Enzyme and Protein Technology VNU University of Science Vietnam National University 334 Nguyen Trai Street Thanh Xuan Dist Hanoi120000 Viet Nam Department of Theoretical Physics VNU University of Science 334 Nguyen Trai Street Thanh Xuan Dist Hanoi120000 Viet Nam

Allopurinol (ALP), a xanthine oxidase inhibitor, is an FDA-approved urate-lowering medication used to treat Gout, prevent tumor lysis syndrome, and prevent recurrent calcium nephrolithiasis in hyperuricosuria patients. However, it has been known as a common cause of severe cutaneous adverse drug reactions (SCAR) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (HSS/DRESS), especially in patients carrying the Human Leukocyte Antigens allele HLA-B∗58:01, which is more prevalent in Asian population. However, although patients do not carry the HLA-B∗58:01 allele, they still exhibit allopurinol-induced SCAR. Surprisingly, a large number of these patients have the HLA-A∗33:03 allele. In this research, we investigated the binding of ALP to the HLA-A∗33:03 structure using Molecular Dynamics (MD) simulation. Our results showed that the complex of HLA-A∗33:03 and ALP was stable after 100000 ps simulation time. ALP had strong interactions with three important residues locating in the active site of HLA-A∗33:03, which include the seven amino acid residues Val 76, Asp 77, Leu 81, Ile 95, Gln 96, Asp 116, and Tyr 123. This data suggests that ALP has strong binding affinity for this allele. Thus, in addition to HLA-B∗58:01, HLA-A∗33:03 may be a potential screening marker before prescribing Allopurinol for Gout treatment. © Published under licence by IOP Publishing Ltd.

关键词： Genes

Investigating structural features of dimeric SARS-CoV-2 Mpro catalytic site with bound covalent ligands at physiological temperature 47

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Investigating structural features of dimeric SARS-CoV-2 Mpro...

47th Vietnam Conference on Theoretical Physics, VCTP 2022

作者： Lai, Hien T. T. Nguyen, Toan T. Key Laboratory for Multiscale Simulation of Complex Systems Department of Theoretical Physics Faculty of Physics University of Science Vietnam National University - Hanoi 334 Nguyen Trai street Thanh Xuan district Hanoi11400 Viet Nam

The SARS-CoV-2 main protease (Mpro) plays an important role in the viral transcription and replication of the SARS-CoV-2 virus that is causing the Covid-19 pandemic worldwide. Therefore, it represents a very attractive target for drug development for treatment of this disease. It is a cysteine protease because it has in the active site the catalytic dyad composed of cysteine (C145) and histidine (H41). The catalytic site represents the binding site for inhibitors, many of them bind to Mpro with a covalent bond. In this research, structural and physiochemical characteristics of the Mpro binding site are investigated when the ligand 11a is covalently and non-covalently bound. All-atom molecular dynamics (MD) simulations were run for 500 ns at physiological temperature (310 K). It is found that conformations of both the Mpro protein and the ligand are stable during the simulation with covalently bound complex showing stronger stability. When the ligand is covalently bound (its final state), residues that stably interact with the ligand are H41, C145, H163, H164 and E166. The optimal conformation of these residues is stabilized also via the Hbond interactions with the catalytic water present in the Mpro binding site. In the case of the non-covalently bound ligand (state before the covalent bond is formed), the binding site residues retain their conformations similar to the covalent binding site, and they still form Hbonds with the catalytic water, except H41. This residue, instead, adopts a different conformation and looses the Hbond with the catalytic water, leaving more freedom to move to the ligand. We hypothesize that H41 could play a role in guiding the ligand to the optimal position for final covalent bonding. Further analyses are in process to check this hypothesis. These results represent an important basis for studying drug candidates against SARS-CoV-2 by means of computer aided drug design. © Published under licence by IOP Publishing Ltd.

关键词： Ligands

Overcharging of zinc ion in zinc−finger protein structure is needed for DNA binding stability

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arXiv 2019年

作者： Nguyen, Ly Hai Tran, Tuyen Thanh Nguyen, Toan T. Key Laboratory for Multiscale Simulation of Complex Systems VNU University of Science Vietnam National University Hanoi 334 Nguyen Trai street Thanh Xuan Hanoi11416 Viet Nam

The zinc finger structure where a Zn2+ ion binds to 4 cysteine or histidine amino acids in a tetrahedral structure is a very common motif of nucleic acid binding proteins. The corresponding interaction model is present in 3% of the genes of human genome. As a result, zinc finger has been shown to be extremely useful in various therapeutic and research capacities, as well as in biotechnology. In stable configuration, the cysteine amino acids are deprotonated and become negatively charged. This means the Zn2+ ion is overscreened by 4 cysteine charges (overcharged). It is a question of whether this overcharged configuration is also stable when such negatively charged zinc−finger binds to negatively charged DNA molecule. Using all−atom molecular dynamics simulation up to microsecond range of an androgen receptor protein dimer, we investigate how the deprotonated state of cysteine influences its structure, dynamics, and function in binding to DNA molecules. Our results show that the deprotonated state of cysteine residues are essential for mechanical stabilization of the functional, folded conformation. Not only this state stabilizes the protein structure, it also stabilizes the protein-DNA binding complex. The differences in structural and energetic properties of the two (sequence-identical) monomers are also investigated showing the strong influence of DNA on the structure of zinc-fingers upon complexation. Our result has potential impact on better molecular understanding of one of the most common classes of zinc fingers. Copyright © 2019, The Authors. All rights reserved.

关键词： Amino acids

Grand-canonical Monte-Carlo simulation of solutions of salt mixtures: theory and implementation

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arXiv 2017年

作者： Nguyen, Toan T. VNU Key Laboratory"Multiscale Simulation of Complex Systems" Faculty of Physics VNU University of Science Vietnam National University 334 Nguyen Trai Street Thanh Xuan Hanoi School of Physics Georgia Institute of Technology 837 State Street AtlantaGA30332-0430 United States

A Grand-canonical Monte-Carlo simulation method extended to simulate a mixture of salts is presented. Due to charge neutrality requirement of electrolyte solutions, ions must be added to or removed from the system in groups. This leads to some complications compared to regular Grand Canonical simulation. Here, a recipe for simulation of electrolyte solution of salt mixture is presented. It is then implemented to simulate solution of 1:1, 2:1 and 2:2 salts or their mixtures at different concentrations using the primitive ion model. The osmotic pressures of the electrolyte solutions are calculated and shown to depend linearly on the salt concentrations within the concentration range simulated. We also show that at the same concentration of divalent anions, the presence of divalent cations make it easier to insert monovalent cations into the system. This can explain some quantitative differences observed in experiments of the MgCl2 salt mixture and MgSO4 salt mixture. Copyright © 2017, The Authors. All rights reserved.

关键词： Magnesium compounds

Investigating molecular mechanism for the stability of ternary systems containing cetrimide, fatty alcohol and water by using computer simulation

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arXiv 2019年

作者： Hoang, Vu Dang Tran, Hung Huu Phuong, Cao Cong Thi Nguyen, Hue Minh Nguyen, Toan T. Department of Analytical Chemistry and Toxicology Hanoi University of Pharmacy 13-15 Le Thanh Tong Hoan Kiem Hanoi Viet Nam Faculty of Chemistry Center for Computational Science Hanoi National University of Education 136 Xuan Thuy Street Cau Giay Hanoi Viet Nam Faculty of Physics VNU Key Laboratory on Multiscale Simulation of Complex Systems VNU University of Science Vietnam National University 334 Nguyen Trai Street Thanh Xuan Hanoi Viet Nam

Computer simulations using atomistic model are carried out to investigate the stability of ternary systems of pure or mixed fatty alcohols, cetrimide, and water. These semi−solid oil-in-water systems are used as the main component of pharmaceutical creams. Experiments show that the mixed alcohol systems are more stable than pure ones. The current experimental hypothesis is that this is the result of the length mismatch of the alkyl chains. This leads to higher configurational entropy of the chain tip of the longer alcohol molecules. Our simulation results support this hypothesis. The results also show that the shorter alcohol molecules become stiffer with higher values of the deuterium order parameters and smaller area per molecule. The magnitude in fluctuations in the area per molecule also increases in mixed systems, indicating a higher configurational entropy. Analysis of the molecular structure of simulated systems also shows good agreements with experimental data. Copyright © 2019, The Authors. All rights reserved.

关键词： Molecules

Computational study of the effect of protonation states of PSA protein zinc fingers on its DNA binding

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Journal of Physics: Conference Series 2019年第1期1274卷

作者： Nguyen Viet Duc Ly Hai Nguyen Hien T. T. Lai Toan T. Nguyen VNU Key Laboratory for Multiscale Simulation of Complex Systems VNU University of Science Vietnam National University 334 Nguyen Trai street Thanh Xuan Hanoi 11416 VIETNAM

In this study, we investigate the binding of the Zinc finger (ZF) structure on a short DNA molecule. The zinc finger of a protein where a Zn2+ ion binds to 4 cysteine or histidine amino acids in a tetrahedral structure is a very common motif of nucleic acid binding proteins. This structure is ubiquitous and the corresponding interaction model is present in 3% of the genes of human genome. ZF has been shown to be extremely useful in various therapeutic and research capacities, as well as in biotechnology. A recent computational study has shown that isolated zinc finger structure is stable if the cysteine amino acids are in deprotonated state. Here, we investigate how this deprotonated state influences protein structure, dynamics, and function in binding of ZF to short DNA molecules using molecular dynamics simulations in sub-microsecond range. Our results show that the Zn2+ ion and the deprotonated state of cysteine is essential for mechanical stabilization of the functional, folded conformation. Not only this state stabilizes the ZF structure, it also stabilizes the DNA-binding structure. Our result has potential impact on better design of zinc fingers for various biotechnological applications.

关键词：

On the holographic phase transitions at finite topological charge

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arXiv 2020年

作者： Phat, Tran Huu Nguyen, Toan T. Vietnam Atomic Energy Commission 59 Ly Thuong Kiet Hanoi Viet Nam Key Laboratory for Multiscale Simulation of Complex Systems University of Science Vietnam National University Hanoi 334 Nguyen Trai street Thanh Xuan district Hanoi120000 Viet Nam

Exploring the significant impacts of topological charge on the holographic phase transitions and conductivity we start from an Einstein Maxwell system coupled with a charged scalar field in Anti de Sitter spacetime. In our set up, the corresponding black hole (BH) is chosen to be the topological AdS one where the pressure is identified with the cosmological constant [12]. Our numerical computation shows that the process of condensation is favored at finite topological charge and, in particular, the pressure variation in the bulk generates a mechanism for changing the order of phase transitions in the boundary: the second order phase transitions occur at pressures higher than the critical pressure of the phase transition from small to large BHs while they become first order at lower pressures. This property is confirmed with the aid of holographic free energy. Finally, the frequency dependent conductivity exhibits a gap when the phase transition is second order and when the phase transition becomes first order this gap is either reduced or totally lost. Copyright © 2020, The Authors. All rights reserved.

关键词： Holography