scholarly journals Experimental and computational studies on molecular mechanism by which Curcumin allosterically inhibits Dengue protease

2020 ◽  
Author(s):  
Liangzhong Lim ◽  
Mei Dang ◽  
Amrita Roy ◽  
Jian Kang ◽  
Jianxing Song
Keyword(s):  
Molecular Dynamics ◽  
Active Site ◽  
Md Simulations ◽  
Food Additive ◽  
Computational Studies ◽  
Active Conformation ◽  
Allosteric Inhibitors ◽  
Two Component ◽  
Ns3 Protease ◽  
First Time

ABSTRACTFlaviviruses including DENV and ZIKV encode a unique two-component NS2B-NS3 protease essential for maturation/infectivity, thus representing a key target for designing anti-flavivirus drugs. Here for the first time, by NMR and molecular docking, we reveal that Curcumin allosterically inhibits the Dengue protease by binding to a cavity with no overlap with the active site. Further molecular dynamics (MD) simulations decode that the binding of Curcumin leads to unfolding/displacing the characteristic β-hairpin of the C-terminal NS2B and consequently disrupting the closed (active) conformation of the protease. Our study identified a cavity most likely conserved in all flaviviral NS2B-NS3 proteases, which could thus serve as a therapeutic target for discovery/design of small molecule allosteric inhibitors. Moreover, as Curcumin has been used as a food additive for thousands of years in many counties, it can be directly utilized to fight the flaviviral infections and as a promising starting for further design of potent allosteric inhibitors.

scholarly journals Myricetin allosterically inhibits Dengue NS2B-NS3 protease as studied by NMR and MD simulations

2021 ◽  
Author(s):  
Mei Dang ◽  
Jianxing Song
Keyword(s):  
Active Site ◽  
Active Form ◽  
Md Simulations ◽  
Active Conformation ◽  
Allosteric Site ◽  
Allosteric Inhibition ◽  
Inactive Conformation ◽  
Active Site Pocket ◽  
Nmr Study ◽  
Ns3 Protease

Dengue NS2B-NS3 protease existing in equilibrium between the active and inactive forms is essential for virus replication, thus representing a key drug target. Here Myricetin, a plant flavonoid, was characterized to non-competitively inhibit Dengue protease. Further NMR study identified the protease residues perturbed by binding to Myricetin, which were utilized to construct the Myricetin-protease complexes. Strikingly, in the active form Myricetin binds a new allosteric site (AS2) far away from the active site pocket and allosteric site (AS1) for binding Curcumin, while in the inactive form it binds both AS1 and AS2. To decipher the mechanism for the allosteric inhibition by Myricetin, we conducted molecular dynamics (MD) simulations on different forms of Dengue NS2B-NS3 protease. Unexpectedly, the binding of Myricetin to AS2 is sufficient to disrupt the active conformation by displacing the characteristic NS2B C-terminal b- hairpin from the active site pocket. By contrast, the binding of Myricetin to AS1 and AS2 results in locking the inactive conformation. Therefore Myricetin represents the first small molecule which allosterically inhibits Dengue protease by both disrupting the active conformation and locking the inactive conformation. The results enforce the notion that a global allosteric network exists in Dengue NS2B-NS3 protease, which is susceptible to allosteric inhibition by small molecules such as Myricetin and Curcumin. As Myricetin has been extensively used as a food additive, it might be directly utilized to fight the Dengue infections and as a promising starting for further design of potent allosteric inhibitors.

Constant-Temperature Molecular-Dynamics Simulation of the 2D Melting Transition of Rb and K

1992 ◽  
Vol 291 ◽  
Author(s):  
J. D. Fan ◽  
Zhi-Xiong Cai
Keyword(s):  
Molecular Dynamics ◽  
Constant Temperature ◽  
Md Simulations ◽  
Dynamics Simulation ◽  
Melting Transition ◽  
Histogram Method ◽  
Graphite Intercalation ◽  
2D System ◽  
Incommensurate Structures ◽  
First Time

ABSTRACTThe energy histogram method, introduced by Ferrenberg and Swendsen [Phys. Rev. Lett., 61, 2635, (1988) and 63, 1195, (1989)], was applied for the first time to the constant temperature molecular dynamics (MD) simulation of a two-dimensional (2D) system with incommensurate structures. We performed MD simulations for the stage-2 graphite intercalation compounds (GIC's) with Rb or K being the intercalants (Rb-GIC's and K- GIC's). The temperature dependence of the specific heat, Cv, is calculated for various sizes up to 864 atoms. The melting temperature was found to be 158 K for Rb-GIC's and 119 K for K-GIC's, respectively, which are in agreement with the experimental observations.

Molecular docking and molecular dynamics simulations of fumarate hydratase and its mutant H235N complexed with pyromellitic acid and citrate

2017 ◽  
Vol 15 (06) ◽  
pp. 1750026 ◽  
Author(s):  
S. Subasri ◽  
Santosh Kumar Chaudhary ◽  
K. Sekar ◽  
Manish Kesherwani ◽  
D. Velmurugan
Keyword(s):  
Molecular Dynamics ◽  
Active Site ◽  
Model Building ◽  
Hydrophobic Interactions ◽  
Conformational Stability ◽  
Fumarate Hydratase ◽  
Md Simulations ◽  
Major Effect ◽  
Active Site Residues ◽  
Pyromellitic Acid

Fumarase catalyzes the reversible, stereospecific hydration/dehydration of fumarate to L-malate during the Kreb’s cycle. In the crystal structure of the tetrameric fumarase, it was found that some of the active site residues S145, T147, N188 G364 and H235 had water-mediated hydrogen bonding interactions with pyromellitic acid and citrate which help to the protonation state for the conversion of fumarate to malate. When His 235 is mutated with Asn (H235N), water-mediated interactions were lost due to the shifting of active site water molecule by 0.7 Å away. Molecular dynamics (MD) simulations were also carried out by NAMD and analyzed using Assisted Model Building with Energy Refinement (AMBER) program to better understand the conformational stability and other aspects during the binding of pyromellitic acid and citrate with native and mutant FH. The role of hydrogen bonds and hydrophobic interactions was also analyzed. The present study confirms that the H235N mutation has a major effect on the catalytic activity of fumarase which is evident from the biochemical studies.

scholarly journals The Study of Boron-Nitride Nanotube Behavior as an Atomic Nano-Pump for Biomedicine Applications

2021 ◽  
Author(s):  
Roozbeh Sabetvand ◽  
Hesamodin Jami
Keyword(s):  
Molecular Dynamics ◽  
Kinetic Energy ◽  
Boron Nitride ◽  
Parameter Optimization ◽  
Fullerene Molecule ◽  
Md Simulations ◽  
Boron Nitride Nanotube ◽  
Equilibrium Process ◽  
First Time ◽  
Excellent Stability

Abstract In this study we use molecular dynamics (MD) simulations to describe the nanopumping process of Boron Nitride Nanotube (BNNT) with fullerene molecule displacement for the first time. Technically, for the simulation of BNNT and fullerene structures, we used Tersoff force-field. The result of the equilibrium process of these structures shows the excellent stability of them which this atomic behavior arises from the appropriate settings in our MD simulations. Further, to describe the BNNT nanopumping process, we calculate the velocity and translational/rotational kinetic energy of fullerene molecule. Numerically, by increasing of simulated structures temperature from 275 K to 350 K, the nanopumping time varies from 9.31 ps to 8.55 ps, respectively. Further, the atomic wave producing in BNNT is an important parameter for nanopumping process and we decrease the nanopumpint time to 7.79 ps by this atomic parameter optimization.

scholarly journals Mechanism of allosteric activation of human mRNA cap methyltransferase (RNMT) by RAM: Insights from accelerated molecular dynamics simulations

2019 ◽  
Author(s):  
Juan A. Bueren-Calabuig ◽  
Marcus Bage ◽  
Victoria H. Cowling ◽  
Andrei V. Pisliakov
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Rna Polymerase Ii ◽  
Active Site ◽  
Allosteric Regulation ◽  
Dynamic Network ◽  
Binding Model ◽  
Accelerated Molecular Dynamics ◽  
Dynamics Simulations ◽  
First Time

ABSTRACTThe RNA guanine-7 methyltransferase (RNMT) in complex with RNMT-Activating Miniprotein (RAM) catalyses the formation of a N7-methylated guanosine cap structure on the 5’ end of nascent RNA polymerase II transcripts. The mRNA cap protects the transcript from exonucleases and recruits cap-binding complexes that mediate RNA processing, export and translation. By using microsecond standard and accelerated molecular dynamics simulations, we provide for the first time a detailed molecular mechanism of allosteric regulation of RNMT by RAM. We show that RAM selects the RNMT active site conformations that are optimal for binding of substrates (AdoMet and the cap), thus enhancing their affinity. Furthermore, our results strongly suggest the likely scenario in which the cap binding promotes the subsequent AdoMet binding, consistent with the previously suggested cooperative binding model. By employing the dynamic network and community analyses, we revealed the underlying long-range allosteric networks and paths that are crucial for allosteric regulation by RAM. Our findings complement and explain previous experimental data on RNMT activity. Moreover, this study provides the most complete description of the cap and AdoMet binding poses and interactions within the enzyme’s active site. This information is critical for the drug discovery efforts that consider RNMT as a promising anti-cancer target.

Interactions of aminoglycoside antibiotics with rRNA

2016 ◽  
Vol 44 (4) ◽  
pp. 987-993 ◽  
Author(s):  
Joanna Trylska ◽  
Marta Kulik
Keyword(s):  
Molecular Dynamics ◽  
Ribosomal Subunit ◽  
Md Simulations ◽  
Aminoglycoside Antibiotics ◽  
Computational Studies ◽  
Gram Negative Bacteria ◽  
Protein Synthesis Inhibitors ◽  
Gram Negative ◽  
Adverse Side Effects ◽  
16S Rna

Aminoglycoside antibiotics are protein synthesis inhibitors applied to treat infections caused mainly by aerobic Gram-negative bacteria. Due to their adverse side effects they are last resort antibiotics typically used to combat pathogens resistant to other drugs. Aminoglycosides target ribosomes. We describe the interactions of aminoglycoside antibiotics containing a 2-deoxystreptamine (2-DOS) ring with 16S rRNA. We review the computational studies, with a focus on molecular dynamics (MD) simulations performed on RNA models mimicking the 2-DOS aminoglycoside binding site in the small ribosomal subunit. We also briefly discuss thermodynamics of interactions of these aminoglycosides with their 16S RNA target.

Molecular dynamics simulations of grain boundary diffusion in Al using embedded atom method potentials

1995 ◽  
Vol 10 (7) ◽  
pp. 1589-1592 ◽  
Author(s):  
Chun-Li Liu ◽  
S.J. Plimpton
Keyword(s):  
Molecular Dynamics ◽  
Grain Boundary ◽  
Boundary Diffusion ◽  
Md Simulations ◽  
Embedded Atom Method ◽  
Melting Temperatures ◽  
Embedded Atom ◽  
Pair Potentials ◽  
Dynamics Simulations ◽  
First Time

Molecular dynamics (MD) simulations of diffusion in a Σ5(310) [001] Al tilt grain boundary were performed using for the first time three different potentials based on the embedded atom method (EAM). The EAM potentials that produce more accurate melting temperatures also yield activation energies in better agreement with experimental data. Compared to pair potentials, the EAM potentials also give more accurate results.

scholarly journals Theoretical insights into the dissociation process for dissociative electron attachment to adenine and its tautomer

2020 ◽  
Vol 38 (4) ◽  
pp. 277-284
Author(s):  
Ying Zhang ◽  
Xing Wang ◽  
Zhongfeng Xu
Keyword(s):  
Molecular Dynamics ◽  
Density Matrix ◽  
Gas Phase ◽  
Electron Attachment ◽  
Closed Shell ◽  
Md Simulations ◽  
Ab Initio Molecular Dynamics ◽  
Dissociative Electron Attachment ◽  
Dissociation Process ◽  
First Time

AbstractThe ab initio molecular dynamics (MD) simulations using an atom-centered density matrix propagation method are carried out in the first time to investigate the dissociative electron attachment (DEA) processes of adenine and its tautomer in the gas phase. Since the incoming electron are captured on the lowest π∗ anti-bond orbital, which is led to the different N–H bond, the C–H bond and the C–N bond are broken. The dominant anion observed in DEA dissociation process is the closed-shell dehydrogenated anion (Ade − H)−. The additional anions (Ade − NH2)− and (Ade − 2H)− are also obtained in ADMP simulation. The results are well consistent with the previous DEA experimental results. Thus, the ADMP method is used to gain a more intuitive and better understanding of the necessary dissociation process in the DEA experiment.

scholarly journals Overlimiting current near a nanochannel a new insight using molecular dynamics simulations

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
D. Manikandan ◽  
Vishal V. R. Nandigana
Keyword(s):  
Molecular Dynamics ◽  
Md Simulations ◽  
Ion Concentration ◽  
Charge Redistribution ◽  
Simulated System ◽  
Dynamics Simulations ◽  
First Time ◽  
Convective Vortices ◽  
Simulation Time ◽  
Overlimiting Current

AbstractIn this paper, we report for the first time overlimiting current near a nanochannel using all-atom molecular dynamics (MD) simulations. Here, the simulated system consists of a silicon nitride nanochannel integrated with two reservoirs. The reservoirs are filled with $${0.1} \, \hbox {M}$$ 0.1 M potassium chloride (KCl) solution. A total of $${\sim } 1.1$$ ∼ 1.1 million atoms are simulated with a total simulation time of $${\sim } 1 {\mu s}$$ ∼ 1 μ s over $${\sim }$$ ∼ 30000 CPU hours using 128 core processors (Intel(R) E5-2670 2.6 GHz Processor). The origin of overlimiting current is found to be due to an increase in chloride ($${Cl^-}$$ C l - ) ion concentration inside the nanochannel leading to an increase in ionic conductivity. Such effects are seen due to charge redistribution and focusing of the electric field near the interface of the nanochannel and source reservoir. Also, from the MD simulations, we observe that the earlier theoretical and experimental postulations of strong convective vortices resulting in overlimiting current are not the true origin for overlimiting current. Our study may open up new theories for the mechanism of overlimiting current near the nanochannel interconnect devices.

Possible mechanisms contributing to oxidative inactivation of activated protein C: Molecular dynamics study

2008 ◽  
Vol 100 (07) ◽  
pp. 18-25 ◽  
Author(s):  
Armen Nalian ◽  
Alexei V. Iakhiaev
Keyword(s):  
Molecular Dynamics ◽  
Active Site ◽  
Protein C ◽  
Activated Protein C ◽  
Md Simulations ◽  
Catalytic Triad ◽  
Methionine Oxidation ◽  
Oxidative Inactivation ◽  
Apc Resistance ◽  
Methionine Residues

SummaryActivated protein C (APC) is a serine protease, an effector enzyme of the natural anticoagulant pathway. APC is approved for treatment of severe sepsis characterized by the increased concentrations of H2O2 and hypochlorite. We found that treatment of APC with these oxidants markedly inhibits the cleavage of the APC-specific chromogenic substrate, suggesting that oxidants can induce changes in the structure of the active site of APC. Resistance of oxidant-treated APC to chemical digestion with cyanogen bromide (CNBr) implies that methionine oxidation can at least in part be responsible for inhibition of APC. Since methionine residues, the main targets of oxidants in APC, are not included in the active site, we hypothesize that oxidation induces allosteric changes in the architecture of the catalytic triad of APC. Using molecular dynamics (MD) simulations we found that methionine oxidation alters the distance between cSer 195Oγ and cHis57 Nε2 atoms placing them in positions unfavorable for the catalysis. At the same time, neither distances between Cα atoms of the catalytic triad cAsp102-cHis57-cSer195, nor the overall structure of APC changed significantly after oxidation of the methionine residues. Disruption of the H-bond between Nδ1 of cHis57 and carboxyl group of cAsp 102, which can take place during the hypochlorite-induced modification of cHis57,dramatically changed the architecture of the catalytic triad in oxidized APC. This mechanism could contribute to APC inactivation by hypochlorite concurrently with methionine oxidation. These are novel findings, which describe potentially pathophysiologically relevant changes in the functional stability of APC exposed to the oxidative stress.

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