scholarly journals Trypanothione Reductase Gene Mutations in Meglumine Anti-moniate Resistant Isolates from Cutaneous Leishmaniasis Pa-tients Using Molecular Dynamics Method

2020 ◽  
Author(s):  
Fatemeh FOZONGARI ◽  
Abdolhossein DALIMI ◽  
Seid Shahriar ARAB ◽  
Mehrdad BEHMANESH ◽  
Anahita KHAMMARI
Keyword(s):  
Molecular Dynamics ◽  
Active Site ◽  
Three Dimensional ◽  
Gene Mutations ◽  
Skin Lesions ◽  
Trypanothione Reductase ◽  
Reductase Gene ◽  
Clinical Resistance ◽  
Structural Mutations ◽  
Susceptible Populations

Background: In this study, mutations in the tripanothion reductase of Leishmania tropica isolated from Iran was investigated using sequencing and simulation of the enzyme by the molecular dynamic method. Methods: Fifteen susceptible and 15 clinical resistant L. tropica specimens were collected from skin lesions from different regions of Iran in 2017. After DNA extraction, trypanothione reductase (TRYR or TPR), gene fragment was amplified using PCR and sequencing methods. In the case of structural mutations, the components were simulated by molecular dynamics using the GROMACS software. Results: Some structural mutations were observed in 9 amino acids surrounding the active site of the TRYR gene of L. tropica with three-dimensional trypanothione reductase alteration. Conclusion: Change in the active site of TRYR of L. tropica, could probably contribute to the development of resistant L. tropica to glucantime. Because of the likely occurrence of mutations in glucantime as well as the ease of development of L. tropica resistant populations, more samples are needed to demonstrate the relationship between mutations in this enzyme and clinical resistance to glucantime. On the other hand, it is recommended that enzymatic studies be performed to confirm the role of mutation in the function and expression of trypanothione reductase in glucantime resistant and susceptible populations.

Three-dimensional model and molecular dynamics simulation of the active site of the self-splicing intervening sequence of the bacteriophage T4 nrdB messenger RNA

Biochemistry ◽  
1990 ◽  
Vol 29 (45) ◽  
pp. 10317-10322 ◽  
Author(s):  
Lennart Nilsson ◽  
Agneta Aahgren-Staalhandske ◽  
Ann Sofie Sjoegren ◽  
Solveig Hahne ◽  
Britt Marie Sjoeberg
Keyword(s):  
Molecular Dynamics ◽  
Active Site ◽  
Messenger Rna ◽  
Bacteriophage T4 ◽  
Three Dimensional ◽  
The Self ◽  
Dynamics Simulation ◽  
Dimensional Model ◽  
Three Dimensional Model ◽  
Self Splicing

scholarly journals Molecular Dynamics Simulations of the Interaction of Mouse andTorpedoAcetylcholinesterase with Covalent Inhibitors Explain Their Differential Reactivity: Implications for Drug Design

2019 ◽  
Author(s):  
Nellore Bhanu Chandar ◽  
Irena Efremenko ◽  
Israel Silman ◽  
Jan M.L. Martin ◽  
Joel L. Sussman
Keyword(s):  
Molecular Dynamics ◽  
Drug Design ◽  
Molecular Dynamics Simulations ◽  
Active Site ◽  
Three Dimensional ◽  
Docking Studies ◽  
Covalent Modification ◽  
Phenylmethylsulfonyl Fluoride ◽  
Living Organisms ◽  
Dynamics Simulations

AbstractAlthough the three-dimensional structures of mouse andTorpedo californicaacetylcholinesterase are very similar, their responses to the covalent sulfonylating agents benzenesulfonyl fluoride and phenylmethylsulfonyl fluoride are qualitatively different. Both agents inhibit the mouse enzyme effectively by covalent modification of its active-site serine. In contrast, whereas theTorpedoenzyme is effectively inhibited by benzenesulfonyl fluoride, it is completely resistant to phenylmethylsulfonyl fluoride. A bottleneck midway down the active-site gorge in both enzymes restricts access of ligands to the active site at the bottom of the gorge. Molecular dynamics simulations revealed that the mouse enzyme is substantially more flexible than theTorpedoenzyme, suggesting that enhanced ‘breathing motions’ of the mouse enzyme relative to theTorpedoenzyme might explain why phenylmethylsulfonyl fluoride can reach the active site in mouse acetylcholinesterase, but not in theTorpedoenzyme. Accordingly, we performed docking of the two sulfonylating agents to the two enzymes, followed by molecular dynamics simulations. Whereas benzenesulfonyl fluoride closely approached the active-site serine in both mouse andTorpedoacetylcholinesterase in such simulations, phenylmethylsulfonyl fluoride was able to approach the active-site serine of mouse acetylcholinesterase - but remained trapped above the bottleneck in the case of theTorpedoenzyme. Our studies demonstrate that reliance on docking tools in drug design can produce misleading information. Docking studies should, therefore, also be complemented by molecular dynamics simulations in selection of lead compounds.Author summaryEnzymes are protein molecules that catalyze chemical reactions in living organisms, and are essential for their physiological functions. Proteins have well defined three-dimensional structures, but display flexibility; it is believed that this flexibility, known as their dynamics, plays a role in their function. Here we studied the neuronal enzyme acetylcholinesterase, which breaks down the neurotransmitter, acetylcholine. The active site of this enzyme is deeply buried, and accessed by a narrow gorge. A particular inhibitor, phenylmethylsulfonyl fluoride, is known to inhibit mouse acetylcholinesterase, but not that of the electric fish,Torpedo, even though their structures are very similar. A theoretical technique called molecular dynamics (MD) shows that the mouse enzyme is more flexible than theTorpedo enzyme. Furthermore, when the movement of the inhibitor down the gorge towards the active site is simulated using MD, the phenylmethylsulfonyl fluoride can reach the active site in the mouse enzyme, but not in theTorpedoenzyme, in which it remains trapped midway down the gorge. Our study emphasizes the importance of taking into account not only structure, but also dynamics, in designing drugs targeted towards proteins.

Three-dimensional structure and molecular dynamics studies of prorrenin/renin receptor: description of the active site

2015 ◽  
Vol 11 (9) ◽  
pp. 2520-2528
Author(s):  
E. Sánchez-Guerrero ◽  
M. E. Hernández-Campos ◽  
J. Correa-Basurto ◽  
P. López-Sánchez ◽  
L. E. Tolentino-López
Keyword(s):  
Molecular Dynamics ◽  
Active Site ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Specific Receptor ◽  
Renin Angiotensin Aldosterone System ◽  
Renin Angiotensin ◽  
Three Dimensional Structure ◽  
System P

The recent finding of a specific receptor for prorrenin/renin (PRR) has brought new insights into the physiology of the renin–angiotensin–aldosterone system.

scholarly journals A Numerical Study of Sub-Millisecond Integrated Mix-and-Inject Microfluidic Devices for Sample Delivery at Synchrotron and XFELs

2021 ◽  
Vol 11 (8) ◽  
pp. 3404
Author(s):  
Majid Hejazian ◽  
Eugeniu Balaur ◽  
Brian Abbey
Keyword(s):  
Molecular Dynamics ◽  
Flow Rate ◽  
Numerical Study ◽  
Three Dimensional ◽  
Microfluidic Devices ◽  
Liquid Jets ◽  
Mixing Efficiency ◽  
X Ray Diffraction ◽  
Cross Sectional ◽  
Time Required

Microfluidic devices which integrate both rapid mixing and liquid jetting for sample delivery are an emerging solution for studying molecular dynamics via X-ray diffraction. Here we use finite element modelling to investigate the efficiency and time-resolution achievable using microfluidic mixers within the parameter range required for producing stable liquid jets. Three-dimensional simulations, validated by experimental data, are used to determine the velocity and concentration distribution within these devices. The results show that by adopting a serpentine geometry, it is possible to induce chaotic mixing, which effectively reduces the time required to achieve a homogeneous mixture for sample delivery. Further, we investigate the effect of flow rate and the mixer microchannel size on the mixing efficiency and minimum time required for complete mixing of the two solutions whilst maintaining a stable jet. In general, we find that the smaller the cross-sectional area of the mixer microchannel, the shorter the time needed to achieve homogeneous mixing for a given flow rate. The results of these simulations will form the basis for optimised designs enabling the study of molecular dynamics occurring on millisecond timescales using integrated mix-and-inject microfluidic devices.

scholarly journals Structural and functional insights into esterase-mediated macrolide resistance

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Michał Zieliński ◽  
Jaeok Park ◽  
Barry Sleno ◽  
Albert M. Berghuis
Keyword(s):  
Active Site ◽  
Pathogenic Bacteria ◽  
Catalytic Mechanism ◽  
Three Dimensional ◽  
Resistance Mechanisms ◽  
Docking Studies ◽  
Macrolide Resistance ◽  
Flexible Docking ◽  
Sequence Identity ◽  
Substrate Spectrum

AbstractMacrolides are a class of antibiotics widely used in both medicine and agriculture. Unsurprisingly, as a consequence of their exensive usage a plethora of resistance mechanisms have been encountered in pathogenic bacteria. One of these resistance mechanisms entails the enzymatic cleavage of the macrolides’ macrolactone ring by erythromycin esterases (Eres). The most frequently identified Ere enzyme is EreA, which confers resistance to the majority of clinically used macrolides. Despite the role Eres play in macrolide resistance, research into this family enzymes has been sparse. Here, we report the first three-dimensional structures of an erythromycin esterase, EreC. EreC is an extremely close homologue of EreA, displaying more than 90% sequence identity. Two structures of this enzyme, in conjunction with in silico flexible docking studies and previously reported mutagenesis data allowed for the proposal of a detailed catalytic mechanism for the Ere family of enzymes, labeling them as metal-independent hydrolases. Also presented are substrate spectrum assays for different members of the Ere family. The results from these assays together with an examination of residue conservation for the macrolide binding site in Eres, suggests two distinct active site archetypes within the Ere enzyme family.

scholarly journals Molecular Basis of In Vivo Resistance to Sulfadoxine-Pyrimethamine in African Adult Patients Infected withPlasmodium falciparum Malaria Parasites

1998 ◽  
Vol 42 (7) ◽  
pp. 1811-1814 ◽  
Author(s):  
Leonardo K. Basco ◽  
Rachida Tahar ◽  
Pascal Ringwald
Keyword(s):  
Dihydrofolate Reductase ◽  
Point Mutations ◽  
Gene Mutations ◽  
Adult Patients ◽  
Wild Type ◽  
Dihydropteroate Synthase ◽  
Reductase Gene ◽  
Parasite Populations

ABSTRACT In vitro sulfadoxine and pyrimethamine resistance has been associated with point mutations in the dihydropteroate synthase and dihydrofolate reductase domains, respectively, but the in vivo relevance of these point mutations has not been well established. To analyze the correlation between genotype and phenotype, 10 Cameroonian adult patients were treated with sulfadoxine-pyrimethamine and followed up for 28 days. After losses to follow-up (n = 1) or elimination of DNA samples due to mixed parasite populations with pyrimethamine-sensitive and pyrimethamine-resistant profiles (n = 3), parasite genomic DNA from day 0 blood samples of six patients were analyzed by DNA sequencing. Three patients who were cured had isolates characterized by a wild-type or mutant dihydrofolate reductase gene (with one or two mutations) and a wild-type dihydropteroate synthase gene. Three other patients who failed to respond to sulfadoxine-pyrimethamine treatment carried isolates with triple dihydrofolate reductase gene mutations and either a wild-type or a mutant dihydropteroate synthase gene. Three dihydrofolate reductase gene codons (51, 59, and 108) may be reliable genetic markers that can accurately predict the clinical outcome of sulfadoxine-pyrimethamine treatment in Africa.

WHICH IS THE PROTON-SHUTTLE IN ISOXANTHOPTERIN DEAMINASE? QM/MM MD UNDERSTANDING

2013 ◽  
Vol 12 (08) ◽  
pp. 1341002 ◽  
Author(s):  
XIN ZHANG ◽  
MING LEI
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
Hydrogen Bonds ◽  
Proton Transfer ◽  
Glutamic Acid ◽  
Active Site ◽  
Nucleophilic Attack ◽  
Zinc Ions ◽  
Initial Model ◽  
Dynamics Simulations

The deamination process of isoxanthopterin catalyzed by isoxanthopterin deaminase was determined using the combined QM(PM3)/MM molecular dynamics simulations. In this paper, the updated PM3 parameters were employed for zinc ions and the initial model was built up based on the crystal structure. Proton transfer and following steps have been investigated in two paths: Asp336 and His285 serve as the proton shuttle, respectively. Our simulations showed that His285 is more effective than Aap336 in proton transfer for deamination of isoxanthopterin. As hydrogen bonds between the substrate and surrounding residues play a key role in nucleophilic attack, we suggested mutating Thr195 to glutamic acid, which could enhance the hydrogen bonds and help isoxanthopterin get close to the active site. The simulations which change the substrate to pterin 6-carboxylate also performed for comparison. Our results provide reference for understanding of the mechanism of deaminase and for enhancing the deamination rate of isoxanthopterin deaminase.

Sign in / Sign up

Export Citation Format

Share Document