Quantum Mechanics/Molecular Mechanics Studies on the Sulfoxidation of Dimethyl Sulfide by Compound I and Compound 0 of Cytochrome P450: Which Is the Better Oxidant?†

2009 ◽  
Vol 113 (43) ◽  
pp. 11635-11642 ◽  
Author(s):  
Cristina S. Porro ◽  
Michael J. Sutcliffe ◽  
Sam P. de Visser
Keyword(s):  
Quantum Mechanics ◽  
Cytochrome P450 ◽  
Molecular Mechanics ◽  
Dimethyl Sulfide ◽  
Compound I

scholarly journals Quantum Mechanics/Molecular Mechanics Studies on the Relative Reactivities of Compound I and II in Cytochrome P450 Enzymes

2018 ◽  
Vol 19 (7) ◽  
pp. 1974 ◽  
Author(s):  
Verònica Postils ◽  
Maud Saint-André ◽  
Amy Timmins ◽  
Xiao-Xi Li ◽  
Yong Wang ◽  
...  
Keyword(s):  
Quantum Mechanics ◽  
Cytochrome P450 ◽  
Molecular Mechanics ◽  
Cytochrome P450 Enzymes ◽  
Compound I

scholarly journals Bioengineering of Cytochrome P450 OleTJE: How Does Substrate Positioning Affect the Product Distributions?

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2675 ◽  
Author(s):  
Fabián G. Cantú Reinhard ◽  
Yen-Ting Lin ◽  
Agnieszka Stańczak ◽  
Sam P. de Visser
Keyword(s):  
Quantum Mechanics ◽  
Molecular Mechanics ◽  
Active Site ◽  
Density Functional ◽  
Computational Study ◽  
Cation Radical ◽  
Wild Type ◽  
Compound I ◽  
Substrate Activation ◽  
Product Distributions

The cytochromes P450 are versatile enzymes found in all forms of life. Most P450s use dioxygen on a heme center to activate substrates, but one class of P450s utilizes hydrogen peroxide instead. Within the class of P450 peroxygenases, the P450 OleTJE isozyme binds fatty acid substrates and converts them into a range of products through the α-hydroxylation, β-hydroxylation and decarboxylation of the substrate. The latter produces hydrocarbon products and hence can be used as biofuels. The origin of these product distributions is unclear, and, as such, we decided to investigate substrate positioning in the active site and find out what the effect is on the chemoselectivity of the reaction. In this work we present a detailed computational study on the wild-type and engineered structures of P450 OleTJE using a combination of density functional theory and quantum mechanics/molecular mechanics methods. We initially explore the wild-type structure with a variety of methods and models and show that various substrate activation transition states are close in energy and hence small perturbations as through the protein may affect product distributions. We then engineered the protein by generating an in silico model of the double mutant Asn242Arg/Arg245Asn that moves the position of an active site Arg residue in the substrate-binding pocket that is known to form a salt-bridge with the substrate. The substrate activation by the iron(IV)-oxo heme cation radical species (Compound I) was again studied using quantum mechanics/molecular mechanics (QM/MM) methods. Dramatic differences in reactivity patterns, barrier heights and structure are seen, which shows the importance of correct substrate positioning in the protein and the effect of the second-coordination sphere on the selectivity and activity of enzymes.

scholarly journals Quantum Mechanics/Molecular Mechanics Modeling of Drug Metabolism: Mexiletine N-Hydroxylation by Cytochrome P450 1A2

2016 ◽  
Vol 29 (6) ◽  
pp. 963-971 ◽  
Author(s):  
Richard Lonsdale ◽  
Rachel M. Fort ◽  
Patrik Rydberg ◽  
Jeremy N. Harvey ◽  
Adrian J. Mulholland
Keyword(s):  
Quantum Mechanics ◽  
Cytochrome P450 ◽  
Drug Metabolism ◽  
Molecular Mechanics ◽  
Cytochrome P450 1A2

scholarly journals Quantum Mechanics/Molecular Mechanics Modeling of Regioselectivity of Drug Metabolism in Cytochrome P450 2C9

2013 ◽  
Vol 135 (21) ◽  
pp. 8001-8015 ◽  
Author(s):  
Richard Lonsdale ◽  
Kerensa T. Houghton ◽  
Jolanta Żurek ◽  
Christine M. Bathelt ◽  
Nicolas Foloppe ◽  
...  
Keyword(s):  
Quantum Mechanics ◽  
Cytochrome P450 ◽  
Drug Metabolism ◽  
Molecular Mechanics ◽  
Cytochrome P450 2C9

On-the-Fly Determination of Active Region Centers in Adaptive-Partitioning QM/MM

2020 ◽  
Author(s):  
Zenghui Yang
Keyword(s):  
Quantum Mechanics ◽  
Active Region ◽  
Molecular Mechanics ◽  
Active Regions ◽  
Available Energy ◽  
Adaptive Partitioning ◽  
Different Levels

Quantum mechanics/molecular mechanics (QM/MM) methods partition the system into active and environmental regions and treat them with different levels of theory, achieving accuracy and efficiency at the same time. Adaptive-partitioning (AP) QM/MM methods allow on-the-fly changes to the QM/MM partitioning of the system. Many of the available energy-based AP-QM/MM methods partition the system according to distances to pre-chosen centers of active regions. For such AP-QM/MM methods, I develop an adaptive-center (AC) method that allows on-the-fly determination of the centers of active regions according to general geometrical or potential-related criteria, extending the range of application of energy-based AP-QM/MM methods to systems where active regions may occur or vanish during the simulation.

A Conserved Asparagine in a Ubiquitin Conjugating Enzyme Positions the Substrate for Nucleophilic Attack

2018 ◽  
Author(s):  
Walker M. Jones ◽  
Aaron G. Davis ◽  
R. Hunter Wilson ◽  
Katherine L. Elliott ◽  
Isaiah Sumner
Keyword(s):  
Molecular Dynamics ◽  
Quantum Mechanics ◽  
Molecular Mechanics ◽  
Reaction Rates ◽  
Nucleophilic Attack ◽  
Classical Molecular Dynamics ◽  
Ubiquitin Conjugating Enzyme ◽  
Conjugating Enzyme

We present classical molecular dynamics (MD), Born-Oppenheimer molecular dynamics (BOMD), and hybrid quantum mechanics/molecular mechanics (QM/MM) data. MD was performed using the GPU accelerated pmemd module of the AMBER14MD package. BOMD was performed using CP2K version 2.6. The reaction rates in BOMD were accelerated using the Metadynamics method. QM/MM was performed using ONIOM in the Gaussian09 suite of programs. Relevant input files for BOMD and QM/MM are available.

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