Computational Study of the Phosphoryl Transfer Catalyzed by a Cyclin-Dependent Kinase

2007 ◽  
Vol 13 (30) ◽  
pp. 8437-8444 ◽  
Author(s):  
Marco De Vivo ◽  
Andrea Cavalli ◽  
Paolo Carloni ◽  
Maurizio Recanatini
Keyword(s):  
Computational Study ◽  
Phosphoryl Transfer ◽  
Cyclin Dependent Kinase

scholarly journals Mechanistic insights into the phosphoryl transfer reaction in cyclin-dependent kinase 2: a QM/MM study

2019 ◽  
Author(s):  
Rodrigo Recabarren ◽  
Edison H. Osorio ◽  
Julio Caballero ◽  
Iñaki Tuñón ◽  
Jans Alzate-Morales
Keyword(s):  
Energy Barrier ◽  
Transfer Reaction ◽  
Theoretical Study ◽  
Phosphoryl Group ◽  
Phosphoryl Transfer ◽  
Cyclin Dependent Kinase ◽  
Peptide Substrate ◽  
Bond Forming ◽  
Potential Energy Barrier ◽  
Charge Analysis

AbstractCyclin-dependent kinase 2 (CDK2) is an important member of the CDK family exerting its most important function in the regulation of the cell cycle. It catalyzes the transfer of the gamma phosphate group from an ATP (adenosine triphosphate) molecule to a Serine/Threonine residue of a peptide substrate. Due to the importance of this enzyme, and protein kinases in general, a detailed understanding of the reaction mechanism is desired. Thus, in this work the phosphoryl transfer reaction catalyzed by CDK2 was revisited and studied by means of hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. Our results show that the base-assisted mechanism is preferred over the substrate-assisted pathway, in agreement with a previous theoretical study. The base-assisted mechanism resulted to be dissociative, with a potential energy barrier of 14.3 kcal/mol, very close to the experimental derived value. An interesting feature of the mechanism is the proton transfer from Lys129 to the phosphoryl group at the second transition state, event that could be helping in neutralizing the charge on the phosphoryl group upon the absence of a second Mg2+ ion. Furthermore, important insights into the mechanisms in terms of bond order and charge analysis were provided. These descriptors helped to characterize the synchronicity of bond forming and breaking events, and to characterize charge transfer effects. Local interactions at the active site are key to modulate the charge distribution on the phosphoryl group and therefore alter its reactivity.

scholarly journals How a Second Mg2+ Ion Affects the Phosphoryl-Transfer Mechanism in a Protein Kinase: A Computational Study

ACS Catalysis ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 169-183
Author(s):  
Rodrigo Recabarren ◽  
Kirill Zinovjev ◽  
Iñaki Tuñón ◽  
Jans Alzate-Morales
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Computational Study ◽  
Transfer Mechanism ◽  
Phosphoryl Transfer ◽  
Kinase A

scholarly journals A computational study of the phosphoryl transfer reaction between ATP and Dha in aqueous solution

2015 ◽  
Vol 13 (40) ◽  
pp. 10179-10190 ◽  
Author(s):  
I. Bordes ◽  
J. J. Ruiz-Pernía ◽  
R. Castillo ◽  
V. Moliner
Keyword(s):  
Aqueous Solution ◽  
Reaction Mechanism ◽  
Transfer Reaction ◽  
Computational Study ◽  
Transfer Reactions ◽  
Phosphoryl Transfer

Phosphoryl transfer reactions are ubiquitous in biology. The reaction mechanism of the phosphorylation of dihydroxyacetone by ATP in aqueous solution has been studied by means of QM/MM simulations in the present paper.

scholarly journals Mechanistic insights into the phosphoryl transfer reaction in cyclin-dependent kinase 2: A QM/MM study

PLoS ONE ◽  
2019 ◽  
Vol 14 (9) ◽  
pp. e0215793 ◽  
Author(s):  
Rodrigo Recabarren ◽  
Edison H. Osorio ◽  
Julio Caballero ◽  
Iñaki Tuñón ◽  
Jans H. Alzate-Morales
Keyword(s):  
Transfer Reaction ◽  
Phosphoryl Transfer ◽  
Cyclin Dependent Kinase

scholarly journals How a Second Mg2+ Ion Affects the Phosphoryl Transfer Mechanism in a Protein Kinase: A Computational Study

2020 ◽  
Author(s):  
Rodrigo Recabarren ◽  
Kirill Zinovjev ◽  
Iñaki Tuñón ◽  
Jans Alzate-Morales
Keyword(s):  
Free Energy ◽  
Quantum Mechanics ◽  
Active Site ◽  
Transfer Reaction ◽  
Computational Study ◽  
Free Energy Calculations ◽  
Phosphoryl Transfer ◽  
Activation Free Energy ◽  
Lower Activation ◽  
Kinase A

<div>In this contribution, the phosphoryl transfer reaction in CDK2 has been studied in detail considering the presence of an additional Mg2+ ion in the active site. For this purpose, QM/MM (quantum mechanics/molecular mechanics) free energy calculations with the adaptive string method were performed, which showed that indeed the system containing two Mg2+ ions exhibits a lower activation free energy, corroborating the experimental observations.</div>

scholarly journals Computational study of the interaction between indene pyrazole and cyclin dependent kinase 2

Química Nova ◽  
2017 ◽  
Author(s):  
Ricardo Vivas-Reyes ◽  
Juan Torres ◽  
Juan Toro ◽  
Rosa Baldiris ◽  
Javier Vergara
Keyword(s):  
Computational Study ◽  
Cyclin Dependent Kinase
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