scholarly journals Catalytic mechanism of the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2)

2021 ◽  
Author(s):  
Li Na Zhao ◽  
Philipp Kaldis
Keyword(s):  
Cancer Cells ◽  
Dehydrogenase Activity ◽  
Catalytic Mechanism ◽  
Computational Study ◽  
Valence Bond ◽  
Water Molecules ◽  
Surrounding Water ◽  
Proton Coupled Electron Transfer ◽  
Methylenetetrahydrofolate Dehydrogenase ◽  
Key Residues

Methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) is a new drug target that is expressed in cancer cells but not in normal adult cells, which provides an Achilles heel to selectively kill cancer cells. Despite the availability of crystal structures of MTHFD2 in the inhibitor- and cofactor-bound forms, key information is missing due to technical limitations, including (a) the location of absolutely required Mg2+ ion, and (b) the substrate-bound form of MTHFD2. Using homology modeling and simulation studies, we propose that two magnesium ions are present at the active site whereby (i) Arg233, Asp225, and two water molecules coordinate MgA, while MgA together with Arg233 stabilize the inorganic phosphate (Pi); (ii) Asp168 and three water molecules coordinate MgB, and MgB further stabilizes Pi by forming a hydrogen bond with two oxygens of Pi; (iii) Arg201 directly coordinates the Pi; and (iv) through three water-mediated interactions, Asp168 contributes to the positioning and stabilization of MgA, MgB and Pi. Our computational study at the empirical valence bond level allowed us to elucidate the detailed reaction mechanisms. We found that the dehydrogenase activity features a proton-coupled electron transfer with charge redistribution coupled to the reorganization of the surrounding water molecules which further facilitates the subsequent cyclohydrolase activity. The cyclohydrolase activity then drives the hydration of the imidazoline ring and the ring opening in a concerted way. Furthermore, we have uncovered that two key residues Ser197/Arg233 are key factors in determining the cofactor (NADP+/NAD+) preference of the dehydrogenase activity. Our work sheds new light on the structural and kinetic framework of MTHFD2, which will be helpful to design small molecule inhibitors that can be used for cancer therapy.

scholarly journals Origin and control of ionic hydration patterns in nanopores

2021 ◽  
Vol 2 (1) ◽  
Author(s):  
Miraslau L. Barabash ◽  
William A. T. Gibby ◽  
Carlo Guardiani ◽  
Alex Smolyanitsky ◽  
Dmitry G. Luchinsky ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Distribution Functions ◽  
Water Molecules ◽  
Surrounding Water ◽  
Ionic Hydration ◽  
Hydration Shells ◽  
Water Layers ◽  
Dynamics Simulations ◽  
And Control

AbstractIn order to permeate a nanopore, an ion must overcome a dehydration energy barrier caused by the redistribution of surrounding water molecules. The redistribution is inhomogeneous, anisotropic and strongly position-dependent, resulting in complex patterns that are routinely observed in molecular dynamics simulations. Here, we study the physical origin of these patterns and of how they can be predicted and controlled. We introduce an analytic model able to predict the patterns in a graphene nanopore in terms of experimentally accessible radial distribution functions, giving results that agree well with molecular dynamics simulations. The patterns are attributable to a complex interplay of ionic hydration shells with water layers adjacent to the graphene membrane and with the hydration cloud of the nanopore rim atoms, and we discuss ways of controlling them. Our findings pave the way to designing required transport properties into nanoionic devices by optimising the structure of the hydration patterns.

Inhibition of Caco-2 and MCF-7 cancer cells using chalcones: synthesis, biological evaluation and computational study

2021 ◽  
pp. 1-7
Author(s):  
Marco Mellado ◽  
Mauricio Reyna-Jeldes ◽  
Caroline Weinstein-Oppenheimer ◽  
Claudio Coddou ◽  
Carlos Jara-Gutierrez ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Computational Study ◽  
Biological Evaluation ◽  
Mcf 7

scholarly journals Combinatorial Library Designing and Virtual Screening of Cryptolepine Derivatives against Topoisomerase II by Molecular Docking

2020 ◽  
Author(s):  
Maria ◽  
Zahid Khan
Keyword(s):  
Molecular Docking ◽  
Cell Division ◽  
Binding Energy ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Combinatorial Library ◽  
Topoisomerase Ii ◽  
Computational Study ◽  
Binding Energies ◽  
Potential Inhibitors

AbstractComputational approaches have emerging role for designing potential inhibitors against topoisomerase 2 for treatment of cancer. TOP2A plays a key role in DNA replication before cell division and thus facilitates the growth of cells. This function of TOP2A can be suppressed by targeting with potential inhibitors in cancer cells to stop the uncontrolled cell division. Among potential inhibitors cryptolepine is more selective and has the ability to intercalate into DNA, effectively block TOP2A and cease cell division in cancer cells. However, cryptolepine is non-specific and have low affinity, therefore, a combinatorial library was designed and virtually screened for identification of its derivatives with greater TOP2A binding affinities.A combinatorial library of 31114 derivatives of cryptolepine was formed and the library was virtually screened by molecular docking to predict the molecular interactions between cryptolepine derivatives and TOP2A taking cryptolepine as standard. The overall screening and docking approach explored all the binding poses of cryptolepine for TOP2A to calculate binding energy. The compounds are given database number 8618, 907, 147, 16755, and 8186 scored lowest binding energies of −9.88kcal/mol, −9.76kcal/mol, −9.75kcal/mol, −9.73kcal/mol, and −9.72kcal/mol respectively and highest binding affinity while cryptolepine binding energy is −6.09kcal/mol. The good binding interactions of the derivatives showed that they can be used as potent TOP2A inhibitors and act as more effective anticancer agents than cryptolepine itself. The interactions of derivatives with different amino acid residues were also observed. A comprehensive understanding of the interactions of proposed derivatives with TOP2A helped for searching more novel and potent drug-like molecules for anticancer therapy. This Computational study suggests useful references to understand inhibition mechanisms that will help in the modification of TOP2A inhibitors.

scholarly journals Ion-water coupling controls class A GPCR signal transduction pathways

2020 ◽  
Author(s):  
Neil J. Thomson ◽  
Owen N. Vickery ◽  
Callum M. Ives ◽  
Ulrich Zachariae
Keyword(s):  
Binding Site ◽  
G Protein ◽  
Signal Transmission ◽  
Water Molecules ◽  
Long Distance ◽  
Protein Binding Region ◽  
Dynamics Simulations ◽  
Key Residues ◽  
Extracellular Sodium ◽  
Communication Pathway

G-protein-coupled receptors (GPCRs) transmit signals across the cell membrane, forming the largest family of membrane proteins in humans. Most GPCRs activate through an evolutionarily conserved mechanism, which involves reorientation of helices and key residues, rearrangement of a hydrogen bonding network mediated by water molecules, and the expulsion of a sodium ion from a protonatable binding site. However, how these components interplay to engage the signal effector binding site remains elusive. Here, we applied information theory to molecular dynamics simulations of pharmaceutically important GPCRs to trace concerted conformational variations across the receptors. We discovered a conserved communication pathway that includes protein residues and cofactors and enables the exchange of information between the extracellular sodium binding site and the intracellular G-protein binding region, coupling the most highly conserved protonatable residues at long distance. Reorientation of internal water molecules was found to be essential for signal transmission along this pathway. By inhibiting protonation, sodium decoupled this connectivity, identifying the ion as a master switch that determines the receptors’ ability to move towards active conformations.

scholarly journals Structural and Functional Analyses of Human ChaC2 in Glutathione Metabolism

Biomolecules ◽  
2019 ◽  
Vol 10 (1) ◽  
pp. 31 ◽  
Author(s):  
Yen T. K. Nguyen ◽  
Joon Sung Park ◽  
Jun Young Jang ◽  
Kyung Rok Kim ◽  
Tam T. L. Vo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Catalytic Mechanism ◽  
Docking Study ◽  
Binding Mode ◽  
Structural Features ◽  
Glutathione Metabolism ◽  
Binding Assays ◽  
Biochemical Analyses ◽  
Functional Analyses

Glutathione (GSH) degradation plays an essential role in GSH homeostasis, which regulates cell survival, especially in cancer cells. Among human GSH degradation enzymes, the ChaC2 enzyme acts on GSH to form 5-l-oxoproline and Cys-Gly specifically in the cytosol. Here, we report the crystal structures of ChaC2 in two different conformations and compare the structural features with other known γ-glutamylcyclotransferase enzymes. The unique flexible loop of ChaC2 seems to function as a gate to achieve specificity for GSH binding and regulate the constant GSH degradation rate. Structural and biochemical analyses of ChaC2 revealed that Glu74 and Glu83 play crucial roles in directing the conformation of the enzyme and in modulating the enzyme activity. Based on a docking study of GSH to ChaC2 and binding assays, we propose a substrate-binding mode and catalytic mechanism. We also found that overexpression of ChaC2, but not mutants that inhibit activity of ChaC2, significantly promoted breast cancer cell proliferation, suggesting that the GSH degradation by ChaC2 affects the growth of breast cancer cells. Our structural and functional analyses of ChaC2 will contribute to the development of inhibitors for the ChaC family, which could effectively regulate the progression of GSH degradation-related cancers.

A computational study on the effect of Ni impurity and O-vacancy on the adsorption and dissociation of water molecules on the surface of anatase (101)

2020 ◽  
Vol 136 ◽  
pp. 109176 ◽  
Author(s):  
Mohammadreza Elahifard ◽  
Hajar Heydari ◽  
Reza Behjatmanesh-Ardakani ◽  
Bijan Peik ◽  
Seyedsaeid Ahmadvand
Keyword(s):  
Computational Study ◽  
Water Molecules ◽  
O Vacancy ◽  
Adsorption And Dissociation

scholarly journals Novel Targeted Anti-Tumor Nanoparticles Developed from Folic Acid-Modified 2-Deoxyglucose

2019 ◽  
Vol 20 (3) ◽  
pp. 697 ◽  
Author(s):  
Shaoming Jin ◽  
Zhongyao Du ◽  
Huiyuan Guo ◽  
Hao Zhang ◽  
Fazheng Ren ◽  
...  
Keyword(s):  
Folic Acid ◽  
Cell Viability ◽  
Cancer Cells ◽  
Water Solubility ◽  
Computational Study ◽  
Biological Effects ◽  
Docking Simulation ◽  
Nano Particles ◽  
Cycle Arrest ◽  
Nano Drug Delivery

The glucose analog, 2-deoxyglucose (2-DG), specifically inhibits glycolysis of cancer cells and interferes with the growth of cancer cells. However, the excellent water solubility of 2-DG makes it difficult to be concentrated in tumor cells. In this study, a targeted nano-pharmacosome was developed with folic acid-modified 2-DG (FA-2-DG) by using amino ethanol as a cleavable linker. FA-2-DG was able to self-assemble, forming nano-particles with diameters of 10–30 nm. The biological effects were evaluated with cell viability assays and flow cytometry analysis. Compared with a physical mixture of folic acid and 2-DG, FA-2-DG clearly reduced cell viability and resulted in cell cycle arrest. A computational study involving docking simulation suggested that FA-2-DG can dock into the same receptor as folic acid, thus confirming that the structural modification did not affect the targeting performance. The results indicated that the nano-pharmacosome consisting of FA-2-DG can be used for targeting in a nano-drug delivery system.

scholarly journals First-Principles Study of AlPO4-H3, a Hydrated Aluminophosphate Zeotype Containing Two Different Types of Adsorbed Water Molecules

Molecules ◽  
2019 ◽  
Vol 24 (5) ◽  
pp. 922 ◽  
Author(s):  
Michael Fischer
Keyword(s):  
Density Functional ◽  
Computational Study ◽  
Pore Space ◽  
Experimental Studies ◽  
Adsorbed Water ◽  
Working Fluid ◽  
Water Molecules ◽  
Small Pore ◽  
Experimental Crystal ◽  
Heat Transformation

Porous aluminophosphate zeotypes (AlPOs) are promising materials for heat transformation applications using water as a working fluid. Two “types” of adsorbed water molecules can be distinguished in hydrated AlPOs: Water molecules adsorbed in the direct proximity of framework aluminium atoms form bonds to these Al atoms, with the coordination number of Al increasing from four to five or six. The remaining water molecules that are adsorbed in other parts of the accessible pore space are not strongly bonded to any framework atom, they interact with their environment exclusively through hydrogen bonds. The APC-type small-pore aluminophosphate AlPO4-H3 contains both types of H2O molecules. In the present work, this prototypical hydrated AlPO is studied using dispersion-corrected density functional theory (DFT) calculations. After validating the computations against experimental crystal structure and Raman spectroscopy data, three interrelated aspects are addressed: First, calculations for various partially hydrated models are used to establish that such partially hydrated phases are not thermodynamically stable, as the interaction with the adsorbed water molecules is distinctly weaker than in fully hydrated AlPO4-H3. Second, IR and Raman spectra are computed and compared to those of the dehydrated analogue AlPO4-C, leading to the identification of a few “fingerprint” modes that could be used as indicators for the presence of Al-coordinated water molecules. Finally, DFT-based molecular dynamics calculations are employed to study the dynamics of the adsorbed water molecules. All in all, this in-depth computational study of AlPO4-H3 contributes to the fundamental understanding of hydrated AlPOs, and should therefore provide valuable information for future computational and experimental studies of these systems.

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