scholarly journals Analysis of Phosphoryl-Transfer Enzymes with QM/MM Free Energy Simulations

2018 ◽  
pp. 53-90 ◽  
Author(s):  
Daniel Roston ◽  
Xiya Lu ◽  
Dong Fang ◽  
Darren Demapan ◽  
Qiang Cui
Keyword(s):  
Free Energy ◽  
Phosphoryl Transfer ◽  
Energy Simulations

scholarly journals Extensive free-energy simulations identify water as the base in nucleotide addition by DNA polymerase

2019 ◽  
Vol 116 (50) ◽  
pp. 25048-25056 ◽  
Author(s):  
Daniel Roston ◽  
Darren Demapan ◽  
Qiang Cui
Keyword(s):  
Free Energy ◽  
Dna Polymerase ◽  
Activation Barrier ◽  
Chemical Mechanism ◽  
Phosphoryl Transfer ◽  
Nucleotide Triphosphates ◽  
Base Mechanism ◽  
Energy Simulations ◽  
Coordinated Water ◽  
Energy Surfaces

Transphosphorylation of nucleotide triphosphates is the central reaction in DNA replication by DNA polymerase as well as many other biological processes. Despite its importance, the microscopic chemical mechanism of transphosphorylation of nucleotide triphosphates is, in most cases, unknown. Here we use extensive simulations of DNA polymerase η to test mechanistic hypotheses. We systematically survey the reactive space by calculating 2D free-energy surfaces for 10 different plausible mechanisms that have been proposed. We supplement these free-energy surfaces with calculations of pKa for a number of potentially acidic protons in different states relevant to the catalytic cycle. We find that among all of the conditions that we test, the smallest activation barrier occurs for a reaction where a Mg2+-coordinated water deprotonates the nucleophilic 3′-OH, and this deprotonation is concerted with the phosphoryl transfer. The presence of a third Mg2+ in the active site lowers the activation barrier for the water-as-base mechanism, as does protonation of the pyrophosphate leaving group, which is consistent with general acid catalysis. The results demonstrate the value of simulations, when used in conjunction with experimental data, to help establish a microscopic chemical mechanism in a complex environment.

Prediction of Alkanolamine pKa Values by Combined Molecular Dynamics Free Energy Simulations and ab initio Calculations

2019 ◽  
Author(s):  
Javad Noroozi ◽  
William Smith
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Ab Initio Calculations ◽  
Gas Phase ◽  
Quantum Chemical ◽  
Phase Reaction ◽  
Pka Values ◽  
Gas Phase Reaction ◽  
Reaction Free Energy ◽  
Energy Simulations

We use molecular dynamics free energy simulations in conjunction with quantum chemical calculations of gas phase reaction free energy to predict alkanolamines pka values. <br>

Specific amino acid recognition by aspartyl-tRNA synthetase studied by free energy simulations 1 1A. R. Fersht

1998 ◽  
Vol 275 (5) ◽  
pp. 823-846 ◽  
Author(s):  
Georgios Archontis ◽  
Thomas Simonson ◽  
Dino Moras ◽  
Martin Karplus
Keyword(s):  
Free Energy ◽  
Amino Acid ◽  
Trna Synthetase ◽  
Specific Amino Acid ◽  
Energy Simulations ◽  
Amino Acid Recognition

scholarly journals Reconciling NMR Structures of the HIV-1 Nucleocapsid Protein (NCp7) using Extensive Polarizable Force Field Free-Energy Simulations

2020 ◽  
Author(s):  
Léa El Khoury ◽  
Frédéric Célerse ◽  
Louis Lagardere ◽  
Luc-Henri Jolly ◽  
Étienne Derat ◽  
...  
Keyword(s):  
Free Energy ◽  
Nucleocapsid Protein ◽  
Extended Form ◽  
Polarizable Force Field ◽  
Relative Free Energy ◽  
Nmr Structures ◽  
Reference Protein ◽  
Energy Simulations ◽  
Hiv 1 ◽  
Most Probable Structure

Using polarizable (AMOEBA) and non-polarizable (CHARMM) force fields, we compare the relative free-energy stability of two extreme conformations of the HIV-1 NCp7 nucleocapsid that had been previously experimentally advocated to prevail in solution. Using accelerated sampling techniques, we show that they differ in stability by no more than 0.75-1.9 kcal/mol depending on the reference protein sequence. While the extended form appears to be the most probable structure, both forms should thus coexist in water explaining the differing NMR findings.<br>

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