scholarly journals Octahedral Trifluoromagnesate, an Anomalous Metal Fluoride Species, Stabilizes the Transition State in a Biological Motor

ACS Catalysis ◽  
2021 ◽  
pp. 2769-2773
Author(s):  
Mengyu Ge ◽  
Robert W. Molt ◽  
Huw T. Jenkins ◽  
G. Michael Blackburn ◽  
Yi Jin ◽  
...  
Keyword(s):  
Transition State ◽  
Metal Fluoride ◽  
Biological Motor

scholarly journals An Unprecedented Octahedral Trifluoromagnesate MgF3(Wat)– Transition State Analog Reveals The Molecular Mechanism of ATP Hydrolysis by Zika Virus Helicase

2020 ◽  
Author(s):  
Mengyu Ge ◽  
Robert W. Molt Jr ◽  
Huw T. Jenkins ◽  
G. Michael Blackburn ◽  
Yi Jin ◽  
...  
Keyword(s):  
Transition State ◽  
Zika Virus ◽  
Active Sites ◽  
Atp Hydrolysis ◽  
Structural Data ◽  
Data Interpretation ◽  
Phosphoryl Group ◽  
Metal Fluoride ◽  
Catalytic Core ◽  
Transition State Analog

Metal fluoride complexes mimic the transferring phosphoryl group in many enzyme-catalyzed reactions. We here employ the trifluoromagnesate transition state analog (TSA) to study a Zika virus NS3h helicase, which uses energy from ATP hydrolysis to reorganize ssRNA leading to completion of virus replication. The crystal structure of this TSA complex displays two conformations for a catalytically important loop, demonstrating how ATP hydrolysis can be coupled with RNA translocation. Unexpectedly, the trifluoromagnesate core of this transition state complex is octahedral. It is identified as having an unprecedented MgF<sub>3</sub>(Wat)<sup>–</sup> ligand, confirmed by <sup>19</sup>F NMR analysis. This structure was further probed by quantum mechanical calculations of the catalytic core (200 atoms), confirming the structural data interpretation and the concerted mechanism of ATP hydrolysis by this class of helicase. The formation of this MgF<sub>3</sub>(Wat)<sup>–</sup> ligand in helicase but not in other multiple MF<sub>x</sub> structures for ATPases and GTPases strongly implies they cannot possess such an additional water in their active sites.

scholarly journals An Unprecedented Octahedral Trifluoromagnesate MgF3(Wat)– Transition State Analog Reveals The Molecular Mechanism of ATP Hydrolysis by Zika Virus Helicase

2020 ◽  
Author(s):  
Mengyu Ge ◽  
Robert W. Molt Jr ◽  
Huw T. Jenkins ◽  
G. Michael Blackburn ◽  
Yi Jin ◽  
...  
Keyword(s):  
Transition State ◽  
Zika Virus ◽  
Active Sites ◽  
Atp Hydrolysis ◽  
Structural Data ◽  
Data Interpretation ◽  
Phosphoryl Group ◽  
Metal Fluoride ◽  
Catalytic Core ◽  
Transition State Analog

Metal fluoride complexes mimic the transferring phosphoryl group in many enzyme-catalyzed reactions. We here employ the trifluoromagnesate transition state analog (TSA) to study a Zika virus NS3h helicase, which uses energy from ATP hydrolysis to reorganize ssRNA leading to completion of virus replication. The crystal structure of this TSA complex displays two conformations for a catalytically important loop, demonstrating how ATP hydrolysis can be coupled with RNA translocation. Unexpectedly, the trifluoromagnesate core of this transition state complex is octahedral. It is identified as having an unprecedented MgF<sub>3</sub>(Wat)<sup>–</sup> ligand, confirmed by <sup>19</sup>F NMR analysis. This structure was further probed by quantum mechanical calculations of the catalytic core (200 atoms), confirming the structural data interpretation and the concerted mechanism of ATP hydrolysis by this class of helicase. The formation of this MgF<sub>3</sub>(Wat)<sup>–</sup> ligand in helicase but not in other multiple MF<sub>x</sub> structures for ATPases and GTPases strongly implies they cannot possess such an additional water in their active sites.

scholarly journals MgF3− and AlF4− transition state analogue complexes of yeast phosphoglycerate kinase

2017 ◽  
Vol 95 (2) ◽  
pp. 295-303
Author(s):  
Nicole E. McCormick ◽  
Stephanie M. Forget ◽  
Raymond T. Syvitski ◽  
David L. Jakeman
Keyword(s):  
Nmr Spectroscopy ◽  
Transition State ◽  
Chemical Shifts ◽  
Phosphoglycerate Kinase ◽  
Indirect Evidence ◽  
Metal Fluoride ◽  
Binding Affinities ◽  
Transition State Analogue ◽  
Transition State Analogues ◽  
Proton Chemical Shifts

The phospho-transfer mechanism of yeast phosphoglycerate kinase (PGK) has been probed through formation of trifluoromagnesate (MgF3−) and tetrafluoroaluminate (AlF4−) transition state analogue complexes and analyzed using 19F, 1H waterLOGSY and 1H chemical shift perturbation NMR spectroscopy. We observed the first 19F NMR spectroscopic evidence for the formation of metal fluoride transition state analogues of yeast PGK and also observed significant changes to proton chemical shifts of PGK in the presence, but not in the absence, of fluoride upon titration of ligands, providing indirect evidence of the formation of a closed ternary transition state. WaterLOGSY NMR spectroscopy experiments using an uncompetitive model were used in an attempt to measure ligand binding affinities within the transition state analogue complexes.

Memapsin 2, a drug target for Alzheimer's disease

2003 ◽  
Vol 70 ◽  
pp. 213-220 ◽  
Author(s):  
Gerald Koelsch ◽  
Robert T. Turner ◽  
Lin Hong ◽  
Arun K. Ghosh ◽  
Jordan Tang
Keyword(s):  
Crystal Structure ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transition State ◽  
Amyloid Precursor Protein ◽  
Therapeutic Target ◽  
Drug Target ◽  
Aspartic Protease ◽  
Precursor Protein ◽  
Memapsin 2

Mempasin 2, a ϐ-secretase, is the membrane-anchored aspartic protease that initiates the cleavage of amyloid precursor protein leading to the production of ϐ-amyloid and the onset of Alzheimer's disease. Thus memapsin 2 is a major therapeutic target for the development of inhibitor drugs for the disease. Many biochemical tools, such as the specificity and crystal structure, have been established and have led to the design of potent and relatively small transition-state inhibitors. Although developing a clinically viable mempasin 2 inhibitor remains challenging, progress to date renders hope that memapsin 2 inhibitors may ultimately be useful for therapeutic reduction of ϐ-amyloid.

Collisional dynamics of Ca1D + HBr reactions: evidence for transition-state motions

1999 ◽  
Vol 97 (8) ◽  
pp. 967-976 ◽  
Author(s):  
M. Garay Salazar, J. M. Orea Rocha, A.
Keyword(s):  
Transition State ◽  
Collisional Dynamics

Reactions of an Aluminium(I) Reagent with 1,2-, 1,3- and 1,5-Dienes: Dearomatisation, Reversibility, and a Pericyclic Mechanism

2019 ◽  
Author(s):  
Clare Bakewell ◽  
Martí Garçon ◽  
Richard Y Kong ◽  
Louisa O'Hare ◽  
Andrew J. P. White ◽  
...  
Keyword(s):  
Reaction Mechanism ◽  
Dft Calculations ◽  
Transition State ◽  
Reaction Pathways ◽  
Aromatic Rings ◽  
Aromatic Character ◽  
Pericyclic Reaction

The reactions of an aluminium(I) reagent with a series of 1,2-, 1,3- and 1,5-dienes are reported. In the case of 1,3-dienes the reaction occurs by a pericyclic reaction mechanism, specifically a cheletropic cycloaddition, to form aluminocyclopentene containing products. This mechanism has been interrogated by stereochemical experiments and DFT calculations. The stereochemical experiments show that the (4+1) cycloaddition follows a suprafacial topology, while calculations support a concerted albeit asynchronous pathway in which the transition state demonstrates aromatic character. Remarkably, the substrate scope of the (4+1) cycloaddition includes dienes that are either in part, or entirely, contained within aromatic rings. In these cases, reactions occur with dearomatisation of the substrate and can be reversible. In the case of 1,2- or 1,5-dienes complementary reactivity is observed; the orthogonal nature of the C=C π-bonds (1,2-diene) and the homoconjugated system (1,5-diene) both disfavour a (4+1) cycloaddition. Rather, reaction pathways are determined by an initial (2+1) cycloaddition to form an aluminocyclopropane intermediate which can in turn undergo insertion of a further C=C π-bond leading to complex organometallic products that incorporate fused hydrocarbon rings.

Active Learning Accelerates Ab Initio Molecular Dynamics on Pericyclic Reactive Energy Surfaces

2020 ◽  
Author(s):  
Shi Jun Ang ◽  
Wujie Wang ◽  
Daniel Schwalbe-Koda ◽  
Simon Axelrod ◽  
Rafael Gomez-Bombarelli
Keyword(s):  
Molecular Dynamics ◽  
Potential Energy ◽  
Transition State ◽  
Potential Energy Surface ◽  
Ab Initio ◽  
Energy Surface ◽  
Computational Cost ◽  
Reactive Trajectories ◽  
Dynamics Simulations ◽  
Energy Surfaces

<div>Modeling dynamical effects in chemical reactions, such as post-transition state bifurcation, requires <i>ab initio</i> molecular dynamics simulations due to the breakdown of simpler static models like transition state theory. However, these simulations tend to be restricted to lower-accuracy electronic structure methods and scarce sampling because of their high computational cost. Here, we report the use of statistical learning to accelerate reactive molecular dynamics simulations by combining high-throughput ab initio calculations, graph-convolution interatomic potentials and active learning. This pipeline was demonstrated on an ambimodal trispericyclic reaction involving 8,8-dicyanoheptafulvene and 6,6-dimethylfulvene. With a dataset size of approximately</div><div>31,000 M062X/def2-SVP quantum mechanical calculations, the computational cost of exploring the reactive potential energy surface was reduced by an order of magnitude. Thousands of virtually costless picosecond-long reactive trajectories suggest that post-transition state bifurcation plays a minor role for the reaction in vacuum. Furthermore, a transfer-learning strategy effectively upgraded the potential energy surface to higher</div><div>levels of theory ((SMD-)M06-2X/def2-TZVPD in vacuum and three other solvents, as well as the more accurate DLPNO-DSD-PBEP86 D3BJ/def2-TZVPD) using about 10% additional calculations for each surface. Since the larger basis set and the dynamic correlation capture intramolecular non-covalent interactions more accurately, they uncover longer lifetimes for the charge-separated intermediate on the more accurate potential energy surfaces. The character of the intermediate switches from entropic to thermodynamic upon including implicit solvation effects, with lifetimes increasing with solvent polarity. Analysis of 2,000 reactive trajectories on the chloroform PES shows a qualitative agreement with the experimentally-reported periselectivity for this reaction. This overall approach is broadly applicable and opens a door to the study of dynamical effects in larger, previously-intractable reactive systems.</div>

An Alternate Energy-Conserved Pathway for the Morita-Baylis-Hillman (MBH) Reaction

2020 ◽  
Author(s):  
Veejendra Yadav
Keyword(s):  
Proton Transfer ◽  
Transition State ◽  
Lower Energy ◽  
Aldol Reaction ◽  
Membered Ring ◽  
Ammonium Ion ◽  
Alternate Energy ◽  
Ring Transition State ◽  
Mbh Reaction

An new overall lower energy pathway for the amine-catalysed Morita-Baylis-Hillman reaction is proposed from computations at the M06-2X/6-311++G(d,p) level. The pathway involves proton-transfer from the ammonium ion to the alkoxide formed from the aldol reaction through a seven-membered ring transition state (TS) structure followed by highly exothermic Hofmann<i> </i>elimination through a five-membered ring TS structure to form the product and also release the catalyst to carry on with the process all over again.

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