Phosphoryl transfer model reactions

The AMl/d-PhoT model [33] is a parameterization of a modified AMl/d Hamiltonian developed specifically to model phosphoryl transfer reactions catalyzed by enzymes and ribozymes for use in linear-scaling calculations and combined QM/MM simulations. The model is currently parametrized for H, O, and P atoms to reproduce... 

Smooth COSMO solvation model. We have recently extended our smooth COSMO solvation model with analytical gradients [71] to work with semiempirical QM and QM/MM methods within the CHARMM and MNDO programs [72, 73], The method is a considerably more stable implementation of the conventional COSMO method for geometry optimizations, transition state searches and potential energy surfaces [72], The method was applied to study dissociative phosphoryl transfer reactions [40], and native and thio-substituted transphosphorylation reactions [73] and compared with density-functional and hybrid QM/MM calculation results. The smooth COSMO method can be formulated as a linear-scaling Green s function approach [72] and was applied to ascertain the contribution of phosphate-phosphate repulsions in linear and bent-form DNA models based on the crystallographic structure of a full turn of DNA in a nucleosome core particle [74],... 

Case Study Comparison of DFT Functionals on Model Phosphoryl Transfer Reactions... 

Simple additions of such labile aquo ions as Mg, Ca, Zn and Mn "1", which are of importance in enzymic phosphoryl transfer, have resulted in only very modest catalytic effects for reactions of phosphate species (3). The much more effective t Com unit possesses the special advantage that it remains intact for long periods, while trans/cis isomerization and substitution in the fifth and sixth coordination sites proceed at moderately rapid and generally convenient rates. These characteristics make it particularly suitable for use in model studies (4). 

A theoretical study based on MP2/6-31+G(d,p) and HF/6-31G(d) ab initio quantum mechanical calculations coupled with Langevin dipoles (LD) and polarised continuum (PCM) solvation models have been carried out by Florian and Warshel [387] to achieve a first systematic study of the free energy surfaces for the hydrolysis of methylphosphate in aqueous solution. The important biological implication of this work is the fact that since the energetics of both the associative and the dissociative mechanics are not too different, the active sites of enzymes can select either mechanism depending on the particular electrostatic environment. This conclusion basically means that both mechanisms should be considered, and this fact seems to contradict some previous studies which have focused on phosphoryl transfer reactions. 

From model studies of the uncatalyzed reactions of GTP and related molecules in solution, the assumption that a base is necessary in the transition state of the Ras-catalyzed reaction has been questioned.195 LFER experiments result in a Bronsted fjniic of 0.07 for the phosphoryl transfer of the y-phosphoryl group from ATP, GTP, and pyrophosphate to a series of alcohols, indicative of very little nucleophilic participation in the transition state.33 The Bronsted P g— — IT for phosphoryl transfer to water from a series of phosphoanhydrides is suggestive of a large degree of bond fission to the leaving group.33 The presence of Mg2+ has no measurable effect on the rates of the model reactions. 

Scheme 5 A model for the mechanism of the phosphotriesterase reaction. The data do not clearly distinguish between a concerted mechanism of phosphoryl transfer, or a phosphorane intermediate in the model above the reaction is shown as a concerted process. In either case, the P-OLg bond is largely broken in the transition state, requiring that breakdown of any putative intermediate is rate-limiting for less activated substrates. For more labile substrates, such as paraoxon, a step involving proton transfer that occurs after phosphoryl transfer is rate-limiting.

This article will consider recent advances in the mechanism of model phosphoryl transfer reactions, magnetic resonance studies of phosphoryl and nucleotidyl transerring enzymes in solution and Xray diffraction studies in the crystalline state which have clarified or at least have suggested the role of the essential divalent cation. 

A recent kinetic study of the catalysis of hydrolysis of phosphorylated pyri-dines by Mg in aqueous solution as a model for enzymic phosphoryl transfer reactions has been reported by Herschlag and Jencks (23). They have provided evidence that a l(y -10 rate enhancement can be obtained in the presence of Mg +. From the analysis, approximately a l(y -fold rate enhancement can be attributed to the greater nucleophilicity of the species Mg(OH)+ compared to... 

In ah initio calculations, the species was modeled separately with MgFj and with P03 as the central moiety. " In the case of MgFj , an energy minimum was obtained with a geometry that corresponded well with the X-ray structure. When modeled as P03 the species is unstable, and resembles instead a transition state for phosphoryl transfer (with a moderate barrier of 14kcalmol ) from substrate G6P to the product glucose-1,6-diphosphate. The computationally modeled reaction is concerted with no phosphorane intermediate. ... 

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