Mechanism of Substrate Activation by Tryptophan Hydroxylase: A Computational Study DOI Creative Commons
Thirakorn Mokkawes, Sam P. de Visser

ChemistryEurope, Journal Year: 2024, Volume and Issue: 3(1)

Published: Nov. 7, 2024

Abstract Serotonin is a hormone that responsible for mood regultion in the brain; however, details on its biosynthetic mechanism remain controversial. Tryptophan hydroxylase catalyzes first step serotonin biosynthesis human body, where it regio‐ and stereoselectively hydroxylates free tryptophan (Trp) amino acid at C 5 ‐position. In this work, we present computational study ranging from molecular dynamics (MD) to quantum mechanics (QM) methods, focused of hydroxylase. An MD simulation an enzyme structure with substrate, co‐substrate dioxygen bound reveals tightly conformation substrate co‐substrate, while protein's three‐dimensional stays virtually intact during simulation. Subsequently, large active‐site cluster models containing more than 200 atoms were created, oxygen atom transfer reactions studied. The calculations predict co‐factor tetrahydrobiopterin binds covalently iron center react molecule form iron(IV)‐oxo species pterin‐4a‐carbinolamine stepwise manner small energy barriers (<5 kcal mol −1 ) along exergonic pathway. However, rate‐determining step, Trp activation through C−O transition state, followed by rapid proton relay produce 5‐hydroxy‐L‐Trp.

Language: Английский

CO2 Adsorption in Natural Deep Eutectic Solvents: Insights from Quantum Mechanics and Molecular Dynamics DOI Creative Commons
Chengxu Zhu, Hannah Wood, Paola Carbone

et al.

Physical Chemistry Chemical Physics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

CO2 capture is an important process for mitigating emissions in the atmosphere. Recently, ionic liquids have been identified as possible systems processes. Major drawbacks of such are mostly high cost synthesis and poor biodegradability. Natural deep eutectic solvents, a class solvents using materials natural origin, developed, which compared to low-cost more environmentally benign. However, very little known on details at molecular level that govern adsorption these what limits features. Elucidating aspects would represent step forward design implementation promising emissions. Herein, we report computational study mechanisms characteristics containing arginine/glycerol mixtures. We establish hydrogen bonding effects drive carbon dioxide composed L-arginine glycerol dynamics quantum mechanics simulations. Our findings indicate that, although both arginine contain multiple atoms capable acting bond donors acceptors, primarily functions acceptor while serves donor most interactions. Furthermore, compounds contribute participate binding. This provides valuable insights into behaviour enhances our understanding from perspective

Language: Английский

Citations

0
Computational Modeling of the Enzymatic Achmatowicz Rearrangement by Heme-Dependent Chloroperoxidase: Reaction Mechanism, Enantiopreference, Regioselectivity, and Substrate Specificity DOI
Fuqiang Chen, Chenghua Zhang, Shiqing Zhang

et al.

Journal of Chemical Information and Modeling, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

The chloroperoxidase from Caldariomyces fumago (CfCPO) catalyzes the oxidative ring expansion of α-heterofunctionalized furans via Achmatowicz rearrangement, providing an elegant tool to convert furan rings into complex-prefunctionalized scaffolds. However, mechanism this transformation remains unclear. Herein, CfCPO-catalyzed reaction rac-1-(2-furyl)ethanol (1a) is studied by quantum chemical calculations and molecular dynamics simulations. reveal that conversion follows general reaction. Notably, binding 1a enzyme's active site influences Compound I (Cpd I) formation, (R)-1a enantiomer results in a lower barrier compared (S)-1a, explaining observed (R)-enantiopreference toward racemic substrate. Additionally, due weaker steric hindrance between porphyrin substrate, nucleophilic attack Cpd on core preferred at less-substituted C4=C5 bond, rationale for experimentally regioselectivity. Finally, bottleneck residues substrate delivery channel also surroundings are proposed be responsible specificity CfCPO. This study lays theoretical foundation rational design new CPOs catalyze rearrangement with broader spectrum or specific stereopreference.

Language: Английский

Citations

0
Defluorination of Fluorophenols by a Heme Dehaloperoxidase: Insights into the Defluorination Mechanism DOI Creative Commons
Yi Zhang, Yuanxin Cao, Chivukula V. Sastri

et al.

ACS Catalysis, Journal Year: 2025, Volume and Issue: unknown, P. 3898 - 3912

Published: Feb. 19, 2025

Language: Английский

Citations

0
Deciphering the Biological Decarboxylation Mechanism of Fatty Acids in Diiron Oxidative Decarboxylase UndA: Key Role of the Adaptive First Coordination Sphere DOI
Yu Sheng, Chao Wang, Hui Chen

et al.

ACS Catalysis, Journal Year: 2025, Volume and Issue: unknown, P. 6772 - 6782

Published: April 11, 2025

Language: Английский

Citations

0
Accessible and predictable QM-cluster model building for enzymes with the Residue Interaction Network Residue Selector DOI
Dominique A. Wappett, Nathan J. DeYonker

Annual reports in computational chemistry, Journal Year: 2024, Volume and Issue: unknown, P. 131 - 155

Published: Jan. 1, 2024

Language: Английский

Citations

2
What is the Origin of the Regioselective C3‐Hydroxylation of L‐Arg by the Nonheme Iron Enzyme Capreomycin C? DOI Creative Commons
Yuanxin Cao, Henrik P. H. Wong, Jim Warwicker

et al.

Chemistry - A European Journal, Journal Year: 2024, Volume and Issue: 30(66)

Published: Aug. 27, 2024

Abstract The nonheme iron dioxygenase capreomycin C (CmnC) hydroxylates a free L‐arginine amino acid regio‐ and stereospecifically at the 3 ‐position as part of antibiotics biosynthesis. Little is known on its structure, catalytic cycle substrate specificity and, therefore, comprehensive computational study was performed. A large QM cluster model CmnC created 297 atoms mechanisms for −H, 4 −H 5 hydroxylation −C desaturation were investigated. All low‐energy pathways correspond to radical reaction with an initial hydrogen atom abstraction followed by OH rebound form alcohol product complexes. work compared alternative L‐Arg hydroxylating dioxygenases differences in active site polarity are compared. We show that tight bonding network binding pocket positions ideal orientation activation, whereby polar groups induce electric field effect guides selectivity.

Language: Английский

Citations

0
Mechanism of Substrate Activation by Tryptophan Hydroxylase: A Computational Study DOI Creative Commons
Thirakorn Mokkawes, Sam P. de Visser

ChemistryEurope, Journal Year: 2024, Volume and Issue: 3(1)

Published: Nov. 7, 2024

Abstract Serotonin is a hormone that responsible for mood regultion in the brain; however, details on its biosynthetic mechanism remain controversial. Tryptophan hydroxylase catalyzes first step serotonin biosynthesis human body, where it regio‐ and stereoselectively hydroxylates free tryptophan (Trp) amino acid at C 5 ‐position. In this work, we present computational study ranging from molecular dynamics (MD) to quantum mechanics (QM) methods, focused of hydroxylase. An MD simulation an enzyme structure with substrate, co‐substrate dioxygen bound reveals tightly conformation substrate co‐substrate, while protein's three‐dimensional stays virtually intact during simulation. Subsequently, large active‐site cluster models containing more than 200 atoms were created, oxygen atom transfer reactions studied. The calculations predict co‐factor tetrahydrobiopterin binds covalently iron center react molecule form iron(IV)‐oxo species pterin‐4a‐carbinolamine stepwise manner small energy barriers (<5 kcal mol −1 ) along exergonic pathway. However, rate‐determining step, Trp activation through C−O transition state, followed by rapid proton relay produce 5‐hydroxy‐L‐Trp.

Language: Английский

Citations

0