Hydrolysis and carbonyl-oxygen exchange in tertiary amides. Estimation of the free energy changes for breakdown and conformational changes of tetrahedral intermediates

1980 ◽  
Vol 58 (20) ◽  
pp. 2167-2172 ◽  
Author(s):  
Pierre Deslongchamps ◽  
Roger Barlet ◽  
Roland J. Taillefer
Keyword(s):  
Free Energy ◽  
Conformational Change ◽  
Conformational Changes ◽  
Rate Constants ◽  
Carbonyl Oxygen ◽  
Intermediate Energy ◽  
Second Order ◽  
Oxygen Exchange ◽  
Basic Hydrolysis ◽  
Tertiary Amides

Second order rate constants were measured at several temperatures for the basic hydrolysis and for concurrent carbonyl-oxygen exchange with solvent for N-benzyl-N-methylformamide-18O, N-benzyl-N-methyltrideutéroacetamide-18O, and N-benzyl-N-methyl-α,α-dideuteropropionamide-18O. Carbonyl-oxygen exchange with solvent is rationalized by invoking a conformational change in the tetrahedral intermediate. Energy barriers for these conformational changes are estimated to be of the order of 5.6, 8.0, 8.2 kcal/mol respectively for the above amides.

Induced conformational change on ferrocenyl-terminated alkyls and their application as transducers for label-free immunosensing of Alzheimer's disease biomarker

RSC Advances ◽  
2016 ◽  
Vol 6 (3) ◽  
pp. 2414-2421 ◽  
Author(s):  
Abdelmoneim Mars ◽  
Wicem Argoubi ◽  
Sami Ben Aoun ◽  
Noureddine Raouafi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Electron Transfer ◽  
Conformational Change ◽  
Conformational Changes ◽  
Rate Constants ◽  
Label Free ◽  
Alkyl Chains ◽  
Disease Biomarker

ApoE Alzheimer's disease biomarker can be sensitively detected by a label-free platform using flexible ferrocene-terminated alkyl chains. The immunorecognition triggers conformational changes, which improve the rate constants of electron-transfer.

Carbonyl oxygen exchange of glycol monoesters. Rate and equilibrium constants for the formation of a tetrahedral intermediate

1979 ◽  
Vol 57 (12) ◽  
pp. 1531-1540 ◽  
Author(s):  
R. A. McClelland ◽  
M. Ahmad ◽  
J. Bohonek ◽  
S. Gedge
Keyword(s):  
Equilibrium Constant ◽  
Rate Constants ◽  
Equilibrium Constants ◽  
Carbonyl Oxygen ◽  
Ester Hydrolysis ◽  
Oxygen Exchange ◽  
Ortho Ester ◽  
Kinetic Investigations ◽  
Relationship Of ◽  
The Relationship

Kinetic investigations of the hydrolysis of the 2-phenyl-4,4,5,5-tetramethyl-1,3-dioxolenium ion and 2-phenyl-2-methoxy-4,4,5,5-tetramethyl-1,3-dioxolane furnish rate constants for all three reaction stages of the ortho ester hydrolysis: (1) generation of the dioxolenium ion, (2) hydration of this ion to form hydrogen ortho ester, and (3) breakdown of this species to pinacol monobenzoate. The equilibrium constant for stage (2) can also be obtained. This study complements a previous investigation of 2-phenyl-2-alkoxy-1,3-dioxolanes where similar information was obtained.The rate constants for carbonyl oxygen exchange of the ester products of these reactions, pinacol monobenzoate and ethylene glycol monobenzoate, have been measured. This reaction is shown to proceed by a different mechanism to that normally associated with exchange of carboxylic acid derivatives: cyclization of the glycol monoester to form hydrogen ortho ester, followed by loss of the labelled exocyclic OH group to give 1,3-dioxolenium ion. Reversal of these steps, initiated by an unlabelled water molecule, results in exchange. The relationship of this mechanism with that of the ortho ester hydrolysis is obvious; it is shown that the exchange provides rate constants for the reverse of stage (3). This means that both the forward and reverse rates of this process have been obtained, and this provides the equilibrium constant.

Hydrolytic behavior of two β-lactams and their corresponding imidate salts. New evidence for stereoelectronic control

1980 ◽  
Vol 58 (19) ◽  
pp. 2061-2068 ◽  
Author(s):  
Pierre Deslongchamps ◽  
Maurice Caron
Keyword(s):  
Sodium Hydroxide ◽  
Carbonyl Oxygen ◽  
Oxygen Exchange ◽  
Hydrochloride Salt ◽  
Stereoelectronic Control ◽  
Acidic Conditions ◽  
Basic Hydrolysis ◽  
New Evidence ◽  
Hydrolysis Of ◽  
Tetrahedral Intermediates

The basic hydrolysis and the concurrent carbonyl–oxygen exchange of 18O-labelled N-phenyl-4-phenyl-2-azetidinone (5*) and N-2,6-dimethylphenyl-2-azetidinone (6*) have been studied. β-Lactam 5* was easily hydrolysed and showed no carbonyl–oxygen exchange with 0.1 N sodium hydroxide (dioxane–water, 9:1). Under the same conditions, β-lactam 6* gave no exchange and was found resistant to basic hydrolysis. Hydrolysis and exchange was observed when 6* was refluxed with 0.1 N and 1 N sodium hydroxide in water.The hydrolysis of the corresponding imidate salts 7 and 8 was also investigated. Under basic conditions, salt 7 gave an 8:2 mixture of ester amine 9 and β-lactam 5, while under acidic conditions the hydrochloride salt of ester amine 9 was the only product. Under basic conditions, the imidate salt 8 produced only the β-lactam 6, and under acidic conditions, a 3:7 mixture of the hydrochloride salt of 10 and β-lactam 6. Under stronger acidic conditions (≥3 N HCl), 8 gave only the starting β-lactam 6.The results of these hydrolysis reactions are easily explained on the basis of the stereoelectronic theory for the cleavage of tetrahedral intermediates, and by taking into account that the nitrogen of tetrahedral intermediates must be either protonated under acidic conditions, or hydrogen bonded with the solvent under basic conditions in order to observe the cleavage of the C—N bond.

An isokinetic relationship in the oxidation of acetals by ozone. Evidence for rotation before the oxidation of acyclic acetals

1979 ◽  
Vol 57 (23) ◽  
pp. 3041-3046 ◽  
Author(s):  
Roland J. Taillefer ◽  
Shirley E. Thomas ◽  
Yves Nadeau ◽  
Helmut Beierbeck
Keyword(s):  
Conformational Change ◽  
Rate Constants ◽  
Second Order ◽  
Experimental Temperature ◽  
Isokinetic Temperature ◽  
Isokinetic Relationship ◽  
Cyclic Acetals ◽  
Temperature Range ◽  
Order Rate ◽  
Experimental Temperature Range

Second order rate constants for the oxidation by ozone of several acyclic acetals of heptaldehyde were determined at several temperatures. An isokinetic relationship is shown to exist for this series of reactions and the isokinetic temperature was found to be below the experimental temperature range, a domain of temperatures where reactivity is dominated by entropy factors. These results are contrasted with those obtained for cyclic acetals of heptaldehyde, where the isokinetic temperature falls above the working temperatures, a domain of temperatures where reactivity depends mainly on enthalpy factors. These results are interpreted in terms of a conformational change before oxidation in the acyclic acetals.

scholarly journals Conformational kinetics reveals affinities of protein conformational states

2015 ◽  
Vol 112 (30) ◽  
pp. 9352-9357 ◽  
Author(s):  
Kyle G. Daniels ◽  
Yang Suo ◽  
Terrence G. Oas
Keyword(s):  
Ligand Binding ◽  
Conformational Change ◽  
Conformational Changes ◽  
Rate Constants ◽  
Conformational Dynamics ◽  
Forward Rate ◽  
Binding Affinities ◽  
Conformational States ◽  
Kinetics Of

Most biological reactions rely on interplay between binding and changes in both macromolecular structure and dynamics. Practical understanding of this interplay requires detection of critical intermediates and determination of their binding and conformational characteristics. However, many of these species are only transiently present and they have often been overlooked in mechanistic studies of reactions that couple binding to conformational change. We monitored the kinetics of ligand-induced conformational changes in a small protein using six different ligands. We analyzed the kinetic data to simultaneously determine both binding affinities for the conformational states and the rate constants of conformational change. The approach we used is sufficiently robust to determine the affinities of three conformational states and detect even modest differences in the protein’s affinities for relatively similar ligands. Ligand binding favors higher-affinity conformational states by increasing forward conformational rate constants and/or decreasing reverse conformational rate constants. The amounts by which forward rate constants increase and reverse rate constants decrease are proportional to the ratio of affinities of the conformational states. We also show that both the affinity ratio and another parameter, which quantifies the changes in conformational rate constants upon ligand binding, are strong determinants of the mechanism (conformational selection and/or induced fit) of molecular recognition. Our results highlight the utility of analyzing the kinetics of conformational changes to determine affinities that cannot be determined from equilibrium experiments. Most importantly, they demonstrate an inextricable link between conformational dynamics and the binding affinities of conformational states.

Inhibition in Purified Systems and in Human Plasma of Chimaeric Plasminogen Activators Consisting of the NH2-Terminal Region of Tissue-Type Plasminogen Activator and the COOH-Terminal Region of UrokinaseType Plasminogen Activator

1988 ◽  
Vol 60 (02) ◽  
pp. 247-250 ◽  
Author(s):  
H R Lijnen ◽  
L Nelles ◽  
B Van Hoef ◽  
F De Cock ◽  
D Collen
Keyword(s):  
Plasminogen Activator ◽  
Rate Constants ◽  
Plasminogen Activators ◽  
Second Order ◽  
Tissue Type ◽  
Single Chain ◽  
Chain Molecules ◽  
Order Rate ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator

SummaryRecombinant chimaeric molecules between tissue-type plasminogen activator (t-PA) and single chain urokinase-type plasminogen activator (scu-PA) or two chain urokinase-type plasminogen activator (tcu-PA) have intact enzymatic properties of scu-PA or tcu-PA towards natural and synthetic substrates (Nelles et al., J Biol Chem 1987; 262: 10855-10862). In the present study, we have compared the reactivity with inhibitors of both the single chain and two chain variants of recombinant u-PA and two recombinant chimaeric molecules between t-PA and scu-PA (t-PA/u-PA-s: amino acids 1-263 of t-PA and 144-411 of u-PA; t-PA/u-PA-e: amino acids 1-274 of t-PA and 138-411 of u-PA). Incubation with human plasma in the absence of a fibrin clot for 3 h at 37° C at equipotent concentrations (50% clot lysis in 2 h), resulted in significant fibrinogen breakdown (to about 40% of the normal value) for all two chain molecules, but not for their single chain counterparts. Preincubation of the plasminogen activators with plasma for 3 h at 37° C, resulted in complete inhibition of the fibrinolytic potency of the two chain molecules but did not alter the potency of the single chain molecules. Inhibition of the two chain molecules occurred with a t½ of approximately 45 min. The two chain variants were inhibited by the synthetic urokinase inhibitor Glu-Gly-Arg-CH2CCl with apparent second-order rate constants of 8,000-10,000 M−1s−1, by purified α2-antiplasmin with second-order rate constants of about 300 M−1s−1, and by plasminogen activator inhibitor-1 (PAI-1) with second-order rate constants of approximately 2 × 107 M−1s−1.It is concluded that the reactivity of single chain and two chain forms of t-PA/u-PA chimaers with inhibitors is very similar to that of the single and two chain forms of intact u-PA.

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>

Hydrogen Atom Transfer Reaction Free Energy as a Predictor of Abiotic Nitroaromatic Reduction Rate Constants: A Comprehensive Analysis

2019 ◽  
Author(s):  
Dominic Di Toro ◽  
Kevin P. Hickey ◽  
Herbert E. Allen ◽  
Richard F. Carbonaro ◽  
Pei C. Chiu
Keyword(s):  
Free Energy ◽  
Hydrogen Atom ◽  
Hydrogen Atom Transfer ◽  
Energy Model ◽  
Second Order ◽  
Transfer Model ◽  
Atom Transfer ◽  
Order Rate ◽  
Linear Free Energy ◽  
Free Energy Model

<div>A linear free energy model is presented that predicts the second order rate constant for the abiotic reduction of nitroaromatic compounds (NACs). For this situation previously presented models use the one electron reduction potential of the NAC reaction. If such value is not available, it has been has been proposed that it could be computed directly or estimated from the electron affinity (EA). The model proposed herein uses the Gibbs free energy of the hydrogen atom transfer (HAT) as the parameter in the linear free energy model. Both models employ quantum chemical computations for the required thermodynamic parameters. The available and proposed models are compared using second order rate constants obtained from five investigations reported in the literature in which a variety of NACs were exposed to a variety of reductants. A comprehensive analysis utilizing all the NACs and reductants demonstrate that the computed hydrogen atom transfer model and the experimental one electron reduction potential model have similar root mean square errors and residual error probability distributions. In contrast, the model using the computed electron affinity has a more variable residual error distribution with a significant number of outliers. The results suggest that a linear free energy model utilizing computed hydrogen transfer reaction free energy produces a more reliable prediction of the NAC abiotic reduction second order rate constant than previously available methods. The advantages of the proposed hydrogen atom transfer model and its mechanistic implications are discussed as well.</div>

Determination of rate constants of redox reactions of second order from current-less potential-time curves by a simplified graphical-numerical method

1983 ◽  
Vol 48 (5) ◽  
pp. 1358-1367 ◽  
Author(s):  
Antonín Tockstein ◽  
František Skopal
Keyword(s):  
Numerical Method ◽  
Explicit Form ◽  
Rate Constant ◽  
Optimization Algorithm ◽  
Rate Constants ◽  
Redox Reactions ◽  
Second Order ◽  
Wide Region ◽  
Recurrent Formula

A method for constructing curves is proposed that are linear in a wide region and from whose slopes it is possible to determine the rate constant, if a parameter, θ, is calculated numerically from a rapidly converging recurrent formula or from its explicit form. The values of rate constants and parameter θ thus simply found are compared with those found by an optimization algorithm on a computer; the deviations do not exceed ±10%.

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