The reaction mechanism of retaining glycosyltransferases

2016 ◽  
Vol 44 (1) ◽  
pp. 51-60 ◽  
Author(s):  
Albert Ardèvol ◽  
Javier Iglesias-Fernández ◽  
Víctor Rojas-Cervellera ◽  
Carme Rovira
Keyword(s):  
Quantum Mechanics ◽  
Reaction Mechanism ◽  
Molecular Mechanics ◽  
Active Site ◽  
Molecular Mechanisms ◽  
Catalytic Mechanism ◽  
Strong Support ◽  
Front Face ◽  
Displacement Reaction ◽  
Displacement Mechanism

The catalytic mechanism of retaining glycosyltransferases (ret-GTs) remains a controversial issue in glycobiology. By analogy to the well-established mechanism of retaining glycosidases, it was first suggested that ret-GTs follow a double-displacement mechanism. However, only family 6 GTs exhibit a putative nucleophile protein residue properly located in the active site to participate in catalysis, prompting some authors to suggest an unusual single-displacement mechanism [named as front-face or SNi (substitution nucleophilic internal)-like]. This mechanism has now received strong support, from both experiment and theory, for several GT families except family 6, for which a double-displacement reaction is predicted. In the last few years, we have uncovered the molecular mechanisms of several retaining GTs by means of quantum mechanics/molecular mechanics (QM/MM) metadynamics simulations, which we overview in the present work.

scholarly journals High-throughput quantum-mechanics/molecular-mechanics (ONIOM) macromolecular crystallographic refinement withPHENIX/DivCon: the impact of mixed Hamiltonian methods on ligand and protein structure

2018 ◽  
Vol 74 (11) ◽  
pp. 1063-1077 ◽  
Author(s):  
Oleg Borbulevych ◽  
Roger I. Martin ◽  
Lance M. Westerhoff
Keyword(s):  
Quantum Mechanics ◽  
Molecular Mechanics ◽  
High Throughput ◽  
Active Site ◽  
Binding Modes ◽  
Acta Cryst ◽  
Structure Based Drug Design ◽  
Energy Functionals ◽  
Conventional Methods ◽  
The Impact

Conventional macromolecular crystallographic refinement relies on often dubious stereochemical restraints, the preparation of which often requires human validation for unusual species, and on rudimentary energy functionals that are devoid of nonbonding effects owing to electrostatics, polarization, charge transfer or even hydrogen bonding. While this approach has served the crystallographic community for decades, as structure-based drug design/discovery (SBDD) has grown in prominence it has become clear that these conventional methods are less rigorous than they need to be in order to produce properly predictive protein–ligand models, and that the human intervention that is required to successfully treat ligands and other unusual chemistries found in SBDD often precludes high-throughput, automated refinement. Recently, plugins to thePython-based Hierarchical ENvironment for Integrated Xtallography(PHENIX) crystallographic platform have been developed to augment conventional methods with thein situuse of quantum mechanics (QM) applied to ligand(s) along with the surrounding active site(s) at each step of refinement [Borbulevychet al.(2014),Acta CrystD70, 1233–1247]. This method (Region-QM) significantly increases the accuracy of the X-ray refinement process, and this approach is now used, coupled with experimental density, to accurately determine protonation states, binding modes, ring-flip states, water positions and so on. In the present work, this approach is expanded to include a more rigorous treatment of the entire structure, including the ligand(s), the associated active site(s) and the entire protein, using a fully automated, mixed quantum-mechanics/molecular-mechanics (QM/MM) Hamiltonian recently implemented in theDivConpackage. This approach was validated through the automatic treatment of a population of 80 protein–ligand structures chosen from the Astex Diverse Set. Across the entire population, this method results in an average 3.5-fold reduction in ligand strain and a 4.5-fold improvement inMolProbityclashscore, as well as improvements in Ramachandran and rotamer outlier analyses. Overall, these results demonstrate that the use of a structure-wide QM/MM Hamiltonian exhibits improvements in the local structural chemistry of the ligand similar to Region-QM refinement but with significant improvements in the overall structure beyond the active site.

A QM/MM study of the catalytic mechanism of succinic semialdehyde dehydrogenase from Synechococcus sp. PCC 7002 and Salmonella typhimurium

RSC Advances ◽  
2015 ◽  
Vol 5 (123) ◽  
pp. 101672-101682 ◽  
Author(s):  
Jing Zhang ◽  
Yongjun Liu
Keyword(s):  
Quantum Mechanics ◽  
Salmonella Typhimurium ◽  
Molecular Mechanics ◽  
Catalytic Mechanism ◽  
Succinic Semialdehyde ◽  
Succinic Semialdehyde Dehydrogenase ◽  
Semialdehyde Dehydrogenase ◽  
Synechococcus Sp

The catalytic mechanism of succinic semialdehyde dehydrogenase (SSADH) has been studied using a combined quantum mechanics and molecular mechanics (QM/MM) approach.

Reaction Mechanism of Human Renin Studied by Quantum Mechanics/Molecular Mechanics (QM/MM) Calculations

ACS Catalysis ◽  
2014 ◽  
Vol 4 (11) ◽  
pp. 3869-3876 ◽  
Author(s):  
Ana R. Calixto ◽  
Natércia F. Brás ◽  
Pedro A. Fernandes ◽  
Maria J. Ramos
Keyword(s):  
Quantum Mechanics ◽  
Reaction Mechanism ◽  
Molecular Mechanics ◽  
Human Renin

Quantum Mechanics/Molecular Mechanics Study of the Sialyltransferase Reaction Mechanism

Biochemistry ◽  
2016 ◽  
Vol 55 (40) ◽  
pp. 5764-5771 ◽  
Author(s):  
Yojiro Hamada ◽  
Yusuke Kanematsu ◽  
Masanori Tachikawa
Keyword(s):  
Quantum Mechanics ◽  
Reaction Mechanism ◽  
Molecular Mechanics

A Quantum Mechanics/Molecular Mechanics Study of the Catalytic Mechanism of the Thymidylate Synthase†

Biochemistry ◽  
2007 ◽  
Vol 46 (12) ◽  
pp. 3704-3713 ◽  
Author(s):  
Natalia Kanaan ◽  
Sergio Martí ◽  
Vicent Moliner ◽  
Amnon Kohen
Keyword(s):  
Quantum Mechanics ◽  
Molecular Mechanics ◽  
Thymidylate Synthase ◽  
Catalytic Mechanism

Quantum mechanics and molecular mechanics study of the reaction mechanism of quorum quenching enzyme: N-acyl homoserine lactonase with C6-HSL

RSC Advances ◽  
2016 ◽  
Vol 6 (28) ◽  
pp. 23396-23402 ◽  
Author(s):  
Shujun Zhang ◽  
Hao Su ◽  
Guangcai Ma ◽  
Yongjun Liu
Keyword(s):  
Quantum Mechanics ◽  
Reaction Mechanism ◽  
Molecular Mechanics ◽  
Lactone Ring ◽  
Quorum Quenching ◽  
Homoserine Lactone ◽  
Ester Bond ◽  
Acyl Homoserine Lactone

N-Acyl-homoserine lactonase fromOchrobactrumsp. strain (AidH) is a novel AHL (N-acyl-homoserine lactone)-lactonase that hydrolyzes the ester bond of the homoserine lactone ring of AHLs.

Reaction Mechanism of Chorismate Mutase Studied by the Combined Potentials of Quantum Mechanics and Molecular Mechanics

2002 ◽  
Vol 106 (46) ◽  
pp. 12059-12065 ◽  
Author(s):  
Yong S. Lee ◽  
Sharon E. Worthington ◽  
Morris Krauss ◽  
Bernard R. Brooks
Keyword(s):  
Quantum Mechanics ◽  
Reaction Mechanism ◽  
Molecular Mechanics ◽  
Chorismate Mutase

scholarly journals Quantum Mechanics/Molecular Mechanics Study of the Reaction Mechanism of Glyoxalase I

2020 ◽  
Vol 59 (4) ◽  
pp. 2594-2603 ◽  
Author(s):  
Sonia Jafari ◽  
Ulf Ryde ◽  
Adam Emad Ahmed Fouda ◽  
Fatemeh Sadat Alavi ◽  
Geng Dong ◽  
...  
Keyword(s):  
Quantum Mechanics ◽  
Reaction Mechanism ◽  
Molecular Mechanics ◽  
Glyoxalase I
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