scholarly journals A Hidden Side of the Conformational Mobility of the Quercetin Molecule Caused by the Rotations of the O3H, O5H and O7H Hydroxyl Groups: In Silico Scrupulous Study

Symmetry ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 230 ◽  
Author(s):  
Ol’ha O. Brovarets’ ◽  
Dmytro M. Hovorun
Keyword(s):  
Energy Barrier ◽  
Conformational Dynamics ◽  
Point Symmetry ◽  
Quantum Mechanical ◽  
Hydroxyl Groups ◽  
Free Energy Barrier ◽  
Quantum Mechanical Theory ◽  
Conformational Transformations ◽  
Orthogonal Orientation ◽  
Conformational Rearrangements

In this study at the MP2/6-311++G(2df,pd)//B3LYP/6-311++G(d,p) level of quantum-mechanical theory it was explored conformational variety of the isolated quercetin molecule due to the mirror-symmetrical hindered turnings of the O3H, O5H and O7H hydroxyl groups, belonging to the A and C rings, around the exocyclic C–O bonds. These dipole active conformational transformations proceed through the 72 transition states (TSs; C1 point symmetry) with non-orthogonal orientation of the hydroxyl groups relatively the plane of the A or C rings of the molecule (HO7C7C8/HO7C7C6 = ±(89.9–93.3), HO5C5C10 = ±(108.9–114.4) and HO3C3C4 = ±(113.6–118.8 degrees) (here and below signs ‘±’ corresponds to the enantiomers)) with Gibbs free energy barrier of activation ΔΔGTS in the range 3.51–16.17 kcal·mol−1 under the standard conditions (T = 298.1 K and pressure 1 atm): ΔΔGTSO7H (3.51–4.27) < ΔΔGTSO3H (9.04–11.26) < ΔΔGTSO5H (12.34–16.17 kcal mol−1). Conformational dynamics of the O3H and O5H groups is partially controlled by the intramolecular specific interactions O3H…O4, C2′/C6′H…O3, O3H…C2′/C6′, O5H…O4 and O4…O5, which are flexible and cooperative. Dipole-active interconversions of the enantiomers of the non-planar conformers of the quercetin molecule (C1 point symmetry) is realized via the 24 TSs with C1 point symmetry (HO3C3C2C1 = ±(11.0–19.1), HC2′/C6′C1′C2 = ±(0.6–2.9) and C3C2C1′C2′/C3C2C1′C6′ = ±(1.7–9.1) degree; ΔΔGTS = 1.65–5.59 kcal·mol−1), which are stabilized by the participation of the intramolecular C2′/C6′H…O1 and O3H…HC2′/C6′ H-bonds. Investigated conformational rearrangements are rather quick processes, since the time, which is necessary to acquire thermal equilibrium does not exceed 6.5 ns.

scholarly journals Substrate Specificity for Human Histidine Methyltransferase SETD3

2021 ◽  
Author(s):  
Jordi Hintzen ◽  
Huida Ma ◽  
Hao Deng ◽  
Apolonia Witecka ◽  
Steffen B. Andersen ◽  
...  
Keyword(s):  
Free Energy ◽  
Energy Barrier ◽  
Human Biology ◽  
Quantum Mechanical ◽  
Enzyme Assays ◽  
Free Energy Barrier ◽  
Methyl Transfer ◽  
Energy Simulations ◽  
Computational Analyses ◽  
Insight Into

Histidine methyltransferase SETD3 plays an important role in human biology and diseases. Previously, we showed that SETD3 catalyzes N3-methylation of histidine 73 in β-actin (Kwiatkowski et al., 2018). Here we report integrated synthetic, biocatalytic, biostructural and computational analyses on human SETD3-catalyzed methylation of β-actin peptides possessing histidine and its structurally and chemically diverse mimics. Our enzyme assays supported by biostructural analyses demonstrate that SETD3 has a broader substrate scope beyond histidine, including N-nucleophiles on the aromatic and aliphatic side chains. Quantum mechanical/molecular mechanical (QM/MM) molecular dynamics and free-energy simulations provide insight into binding geometries and the free energy barrier for the enzymatic methyl transfer to histidine mimics, further supporting experimental data that histidine is the superior SETD3 substrate over its analogs. This work demonstrates that human SETD3 has a potential to catalyze efficient methylation of several histidine mimics, overall providing mechanistic, biocatalytic and functional insight into β-actin histidine methylation by SETD3.

Molecular Basis of Glucose Transport Mechanism in Plants

2019 ◽  
Author(s):  
Balaji Selvam ◽  
Ya-Chi Yu ◽  
Liqing Chen ◽  
Diwakar Shukla
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Transport Mechanism ◽  
Conformational Dynamics ◽  
Site Directed Mutagenesis ◽  
Free Energy Barrier ◽  
Transport Cycle ◽  
Dynamics Simulations

<p>The SWEET family belongs to a class of transporters in plants that undergoes large conformational changes to facilitate transport of sugar molecules across the cell membrane. However, the structures of their functionally relevant conformational states in the transport cycle have not been reported. In this study, we have characterized the conformational dynamics and complete transport cycle of glucose in OsSWEET2b transporter using extensive molecular dynamics simulations. Using Markov state models, we estimated the free energy barrier associated with different states as well as 1 for the glucose the transport mechanism. SWEETs undergoes structural transition to outward-facing (OF), Occluded (OC) and inward-facing (IF) and strongly support alternate access transport mechanism. The glucose diffuses freely from outside to inside the cell without causing major conformational changes which means that the conformations of glucose unbound and bound snapshots are exactly same for OF, OC and IF states. We identified a network of hydrophobic core residues at the center of the transporter that restricts the glucose entry to the cytoplasmic side and act as an intracellular hydrophobic gate. The mechanistic predictions from molecular dynamics simulations are validated using site-directed mutagenesis experiments. Our simulation also revealed hourglass like intermediate states making the pore radius narrower at the center. This work provides new fundamental insights into how substrate-transporter interactions actively change the free energy landscape of the transport cycle to facilitate enhanced transport activity.</p>

DFT study on the hydrolysis of metsulfuron-methyl: A sulfonylurea herbicide

2018 ◽  
Vol 17 (08) ◽  
pp. 1850050 ◽  
Author(s):  
Qiuhan Luo ◽  
Gang Li ◽  
Junping Xiao ◽  
Chunhui Yin ◽  
Yahui He ◽  
...  
Keyword(s):  
Free Energy ◽  
Water Molecule ◽  
Carbonyl Group ◽  
Energy Barrier ◽  
Density Functional ◽  
Free Energy Barrier ◽  
Functional Theory ◽  
Metsulfuron Methyl ◽  
Catalytic Role ◽  
Hydrolysis Of

Sulfonylureas are an important group of herbicides widely used for a range of weeds and grasses control particularly in cereals. However, some of them tend to persist for years in environments. Hydrolysis is the primary pathway for their degradation. To understand the hydrolysis behavior of sulfonylurea herbicides, the hydrolysis mechanism of metsulfuron-methyl, a typical sulfonylurea, was investigated using density functional theory (DFT) at the B3LYP/6-31[Formula: see text]G(d,p) level. The hydrolysis of metsulfuron-methyl resembles nucleophilic substitution by a water molecule attacking the carbonyl group from aryl side (pathway a) or from heterocycle side (pathway b). In the direct hydrolysis, the carbonyl group is directly attacked by one water molecule to form benzene sulfonamide or heterocyclic amine; the free energy barrier is about 52–58[Formula: see text]kcal[Formula: see text]mol[Formula: see text]. In the autocatalytic hydrolysis, with the second water molecule acting as a catalyst, the free energy barrier, which is about 43–45[Formula: see text]kcal[Formula: see text]mol[Formula: see text], is remarkably reduced by about 11[Formula: see text]kcal[Formula: see text]mol[Formula: see text]. It is obvious that water molecules play a significant catalytic role during the hydrolysis of sulfonylureas.

COMPARING FOLDING MECHANISMS OF DIFFERENT PRION PROTEINS BY Gō MODEL

2013 ◽  
Vol 12 (08) ◽  
pp. 1341004
Author(s):  
XUE WU ◽  
TING FU ◽  
ZHI-LONG XIU ◽  
LIU YIN ◽  
JIN-GUANG WANG ◽  
...  
Keyword(s):  
Free Energy ◽  
Prion Protein ◽  
Energy Barrier ◽  
Prion Proteins ◽  
Coarse Grained ◽  
Transmissible Spongiform Encephalopathies ◽  
Free Energy Barrier ◽  
Spongiform Encephalopathies ◽  
Go Model ◽  
Folding Free Energy

Prions are associated with neurodegenerative diseases induced by transmissible spongiform encephalopathies. The infectious scrapie form is referred to as PrP Sc , which has conformational change from normal prion with predominant α-helical conformation to the abnormal PrP Sc that is rich in β-sheet content. Neurodegenerative diseases have been found from both human and bovine sources, but there are no reports about infected by transmissible spongiform encephalopathies from rabbit, canine and horse sources. Here we used coarse-grained Gō model to compare the difference among human, bovine, rabbit, canine, and horse normal (cellular) prion proteins. The denatured state of normal prion has relation with the conversion from normal to abnormal prion protein, so we used all-atom Gō model to investigate the folding pathway and energy landscape for human prion protein. Through using coarse-grained Gō model, the cooperativity of the five prion proteins was characterized in terms of calorimetric criterion, sigmoidal transition, and free-energy profile. The rabbit and horse prion proteins have higher folding free-energy barrier and cooperativity, and canine prion protein has slightly higher folding free-energy barrier comparing with human and bovine prion proteins. The results from all-atom Gō model confirmed the validity of C α-Gō model. The correlations of our results with previous experimental and theoretical researches were discussed.

The role of the basis set and the level of quantum mechanical theory in the prediction of the structure and reactivity of cisplatin

2012 ◽  
Vol 33 (29) ◽  
pp. 2292-2302 ◽  
Author(s):  
Diego Paschoal ◽  
Bruna L. Marcial ◽  
Juliana Fedoce Lopes ◽  
Wagner B. De Almeida ◽  
Hélio F. Dos Santos
Keyword(s):  
Basis Set ◽  
Quantum Mechanical ◽  
Mechanical Theory ◽  
Quantum Mechanical Theory
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