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

Directed Evolution of Protoglobin Optimizes the Enzyme Electric Field DOI
Shobhit S. Chaturvedi, Santiago Vargas, Pujan Ajmera

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(24), P. 16670 - 16680

Published: June 7, 2024

To unravel why computational design fails in creating viable enzymes, while directed evolution (DE) succeeds, our research delves into the laboratory of protoglobin. DE has adapted this protein to efficiently catalyze carbene transfer reactions. We show that previously proposed enhanced substrate access and binding alone cannot account for increased yields during DE. The 3D electric field entire active site is tracked through dynamics, clustered using affinity propagation algorithm, subjected principal component analysis. This analysis reveals notable changes with DE, where distinct topologies influence transition state energetics mechanism. A chemically meaningful emerges takes lead facilitates crossing barrier transfer. Our findings underscore intrinsic dynamic's on enzyme function, ability switch mechanisms within same protein, crucial role design.

Language: Английский

Citations

7
Quantum Mechanical Cluster Models for Calculations on Enzymatic Reaction Mechanisms: Set‐Up and Accuracy DOI Creative Commons
Sam P. de Visser, Henrik P. H. Wong, Yi Zhang

et al.

Chemistry - A European Journal, Journal Year: 2024, Volume and Issue: 30(60)

Published: Aug. 7, 2024

Enzymes turnover substrates into products with amazing efficiency and selectivity as such have great potential for use in biotechnology pharmaceutical applications. However, details of their catalytic cycles the origins surrounding regio- chemoselectivity enzymatic reaction processes remain unknown, which makes engineering enzymes challenging. Computational modelling can assist experimental work field establish factors that influence rates product distributions. A popular approach is quantum mechanical cluster models take first- second coordination sphere enzyme active site consideration. These QM are widely applied but often results obtained dependent on model choice selection. Herein, we show give highly accurate reproduce distributions free energies activation within several kcal mol

Language: Английский

Citations

7
Machine learning-aided engineering of a cytochrome P450 for optimal bioconversion of lignin fragments DOI Creative Commons

Artur Hermano Sampaio Dias,

Yuanxin Cao, Munir S. Skaf

et al.

Physical Chemistry Chemical Physics, Journal Year: 2024, Volume and Issue: 26(25), P. 17577 - 17587

Published: Jan. 1, 2024

Using molecular dynamics, machine learning, and density functional theory calculations we make predictions on engineered cytochrome P450 structures their product distributions.

Language: Английский

Citations

6
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
easyPARM: Automated, Versatile, and Reliable Force Field Parameters for Metal-Containing Molecules with Unique Labeling of Coordinating Atoms DOI
Abdelazim M. A. Abdelgawwad, Antonio Francés‐Monerris

Journal of Chemical Theory and Computation, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 6, 2025

The dynamics of metal centers are challenging to describe due the vast variety ligands, metals, and coordination spheres, hampering existence general databases transferable force field parameters for classical molecular simulations. Here, we present easyPARM, a Python-based tool that can calculate wide range complexes from routine frequency calculations with electronic structure methods. approach is based on unique labeling strategy, in which each ligand atom coordinates receives type. This design prevents parameter shortage, duplication, necessity post-process output files, even very complicated whose parametrization process remain automatic. program requires Cartesian Hessian matrix, geometry xyz file, atomic charges provide reliable force-field extensively benchmarked against density functional theory both gas condensed phases. procedure allows description at low computational cost an accuracy as good quality matrix obtained by quantum chemistry easyPARM v2.00 reads vibrational frequencies Gaussian (version 09 or 16) ORCA 5 6) format provides refined Amber format. These be directly used NAMD engines converted other formats. available free charge GitHub platform (https://github.com/Abdelazim-Abdelgawwad/easyPARM.git).

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
Cluster model study of the mechanism and origins of enantio- and chemoselectivity in non-heme iron enzyme-catalyzed C–H azidation DOI Creative Commons
Hang Liu,

Xiahe Chen,

Hongli Wu

et al.

RSC Advances, Journal Year: 2025, Volume and Issue: 15(12), P. 8931 - 8937

Published: Jan. 1, 2025

Computational insights reveal the origin of enantio- and chemoselectivity in non-heme iron enzyme-catalyzed C–H azidation.

Language: Английский

Citations

0
Mechanism of the Oxidative Ring-Closure Reaction during Gliotoxin Biosynthesis by Cytochrome P450 GliF DOI Open Access

Muizz Qureshi,

Thirakorn Mokkawes, Yuanxin Cao

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 8567 - 8567

Published: Aug. 6, 2024

During gliotoxin biosynthesis in fungi, the cytochrome P450 GliF enzyme catalyzes an unusual C-N ring-closure step while also aromatic ring is hydroxylated same reaction cycle, which may have relevance to drug synthesis reactions biotechnology. However, as details of mechanism are still controversial, no applications been developed yet. To resolve and gain insight into steps leading ring-closure, we ran a combination molecular dynamics density functional theory calculations on structure reactivity tested range possible mechanisms, pathways models. The show that, rather than hydrogen atom transfer from substrate Compound I, initial proton transition state followed by fast electron en route radical intermediate, hence non-synchronous abstraction takes place. intermediate then reacts OH rebound form biradical through between centers, gives products. Interestingly, energetics mechanisms appear little affected addition polar groups model predict that can be catalyzed other isozymes bind substrate. Alternative pathways, such pathway starting with electrophilic attack arene epoxide, high energy ruled out.

Language: Английский

Citations

2
Machine-Learning Prediction of Protein Function from the Portrait of Its Intramolecular Electric Field DOI
Santiago Vargas, Shobhit S. Chaturvedi, Anastassia N. Alexandrova

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 7, 2024

We introduce a machine learning framework designed to predict enzyme functionality directly from the heterogeneous electric fields inherent protein active sites. apply this method curated data set of heme-iron oxidoreductases, spanning three classes: monooxygenases, peroxidases, and catalases. Conventional analysis, focused on simplistic, point along Fe–O bond, is shown be inadequate for accurate activity prediction. Our model demonstrates that enzyme's 3-D field, alone, can accurately its function, without relying additional protein-specific information. Through feature selection, we uncover key field components not only validate previous studies but also underscore crucial role multiple beyond traditionally emphasized bond in heme enzymes. Furthermore, by integrating dynamics, principal component clustering, QM/MM calculations, reveal while dynamic complexities structures obscure predictions, still retains accuracy. This research significantly advances our understanding how scaffolds possess signature tailored their functions at site. Moreover, it presents novel electrostatics-based tool harness these predicting function.

Language: Английский

Citations

2
Probing Ferryl Reactivity in a Nonheme Iron Oxygenase Using an Expanded Genetic Code DOI Creative Commons
Florence J. Hardy, Matthew G. Quesne,

Emilie F. Gérard

et al.

ACS Catalysis, Journal Year: 2024, Volume and Issue: 14(15), P. 11584 - 11590

Published: July 20, 2024

The ability to introduce noncanonical amino acids as axial ligands in heme enzymes has provided a powerful experimental tool for studying the structure and reactivity of their FeIV═O ("ferryl") intermediates. Here, we show that similar approach can be used perturb conserved Fe coordination environment 2-oxoglutarate (2OG) dependent oxygenases, versatile class employ highly-reactive ferryl intermediates mediate challenging C–H functionalizations. Replacement one cis-disposed histidine oxygenase VioC with less electron donating Nδ-methyl-histidine (MeHis) preserves both catalytic function reaction selectivity. Significantly, key intermediate responsible activation accumulated wildtype modified protein. In contrast enzymes, where metal-oxo is extremely sensitive nature proximal ligand, rates observed large kinetic isotope effects are only minimally affected by ligand replacement VioC. This study showcases modulating sphere nonheme iron will enhance our understanding factors governing divergent activities.

Language: Английский

Citations

1