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

10.26434/chemrxiv.12560153 ◽

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>

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Phosphoryl transfer reaction catalyzed by membrane diacylglycerol kinase: a theoretical mechanism study

Physical Chemistry Chemical Physics ◽

10.1039/c5cp03342j ◽

2015 ◽

Vol 17 (38) ◽

pp. 25228-25234 ◽

Cited By ~ 1

Author(s):

Yafei Jiang ◽

Hongwei Tan ◽

Jimin Zheng ◽

Xichen Li ◽

Guangju Chen ◽

...

Keyword(s):

Active Site ◽

Transfer Reaction ◽

Diacylglycerol Kinase ◽

Phosphoryl Transfer ◽

Mechanism Study ◽

Theoretical Mechanism ◽

Kinase A

Despite a unique composite active site formed by two monomers, DgkA catalyzes phosphotransfer reaction using the canonical kinase mechanism.

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Structure and activity of phosphoglycerate mutase

Philosophical Transactions of the Royal Society of London Series B Biological Sciences ◽

10.1098/rstb.1981.0066 ◽

1981 ◽

Vol 293 (1063) ◽

pp. 121-130 ◽

Cited By ~ 70

Keyword(s):

Active Site ◽

Transfer Reaction ◽

Chemical Kinetic ◽

Phosphoglycerate Mutase ◽

Phosphoryl Transfer ◽

X Ray ◽

Histidine Residues ◽

Ping Pong ◽

Available Information ◽

Structure And Activity

The structure of yeast phosphoglycerate mutase determined by X-ray crystallographic and amino acid sequence studies has been interpreted in terms of the chemical, kinetic and mechanistic observations made on this enzyme. There are two histidine residues at the active site, with imidazole groups almost parallel to each other and approximately 0.4 nm apart, positioned close to the 2 and 3 positions of the substrate. The simplest interpretation of the available information suggests that a ping-pong type mechanism operates in which at least one of these histidine residues participates in the phosphoryl transfer reaction. The flexible C-terminal region also plays an important role in the enzymic reaction.

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The molecular mechanism studies of chirality effect of PHA-739358 on Aurora kinase A by molecular dynamics simulation and free energy calculations

Journal of Computer-Aided Molecular Design ◽

10.1007/s10822-010-9408-7 ◽

2011 ◽

Vol 25 (2) ◽

pp. 171-180 ◽

Cited By ~ 18

Author(s):

Yuanhua Cheng ◽

Wei Cui ◽

Quan Chen ◽

Chen-Ho Tung ◽

Mingjuan Ji ◽

...

Keyword(s):

Molecular Dynamics ◽

Free Energy ◽

Molecular Dynamics Simulation ◽

Molecular Mechanism ◽

Aurora Kinase ◽

Free Energy Calculations ◽

Dynamics Simulation ◽

Aurora Kinase A ◽

Energy Calculations ◽

Kinase A

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Physical Nature of Intermolecular Interactions within cAMP-Dependent Protein Kinase Active Site: Differential Transition State Stabilization in Phosphoryl Transfer Reaction

The Journal of Physical Chemistry B ◽

10.1021/jp8040633 ◽

2008 ◽

Vol 112 (37) ◽

pp. 11819-11826 ◽

Cited By ~ 23

Author(s):

Pawel Szarek ◽

Edyta Dyguda-Kazimierowicz ◽

Akitomo Tachibana ◽

W. Andrzej Sokalski

Keyword(s):

Protein Kinase ◽

Transition State ◽

Intermolecular Interactions ◽

Active Site ◽

Transfer Reaction ◽

Physical Nature ◽

Phosphoryl Transfer ◽

Dependent Protein Kinase ◽

Transition State Stabilization ◽

Dependent Protein

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Interaction of lecithin-cholesterol acyltransferase with lipid surfaces and apolipoprotein A-I derived peptides: implications for the cofactor mechanism of apolipoprotein A-I

10.1101/225037 ◽

2017 ◽

Author(s):

Marco G. Casteleijn ◽

Petteri Parkkila ◽

Tapani Viitala ◽

Artturi Koivuniemi

Keyword(s):

Amino Acids ◽

Free Energy ◽

Active Site ◽

Cholesterol Acyltransferase ◽

Lipid Binding ◽

Free Energy Calculations ◽

Coarse Grained ◽

Lecithin Cholesterol Acyltransferase ◽

Apolipoprotein A ◽

Lipid Surface

AbstractLecithin-cholesterol acyltransferase (LCAT) is an enzyme responsible for the formation of cholesteryl esters from cholesterol (CHOL) and phospholipid (PL) molecules in high-density lipoprotein (HDL) particles that play a crucial role in the reverse cholesterol transport and the development of coronary heart disease (CHD). However, it is poorly understood how LCAT interacts with lipoprotein surfaces and how apolipoprotein A-I (apoA-I) activates it. Thus, here we have studied the interactions between LCAT and lipids through extensive atomistic and coarse-grained molecular dynamics simulations to reveal mechanistic details behind the cholesterol esterification process catalyzed by LCAT. In addition, we studied the binding of LCAT to apoA-I derived peptides, and their effect on LCAT lipid association utilizing experimental surface sensitive biophysical methods. Our simulations show that LCAT anchors itself to lipoprotein surfaces by utilizing non-polar amino acids located in the membrane-binding domain and the active site tunnel opening. Meanwhile, the membrane anchoring hydrophobic amino acids attract cholesterol molecules next to them. The results also highlight the role of the lid-loop in the lipid binding and conformation of LCAT with respect to the lipid surface. The apoA-I derived peptides from the LCAT activating region bind to LCAT and promote its lipid surface interactions, although some of these peptides do not bind lipids individually. By means of free-energy calculations we provided a hypothetical explanation for this mechanism. We also found that the transfer free-energy of PL to the active site is consistent with the activation energy of LCAT. Furthermore, the entry of CHOL molecules into the active site becomes highly favorable by the acylation of SER181. The results provide substantial mechanistic insights concerning the activity of LCAT that may lead to the development of novel pharmacological agents preventing CHD in the future.

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