Evidence of a Distinctive Enantioselective Binding Mode for the Photoinduced Radical Cyclization of α-Chloroamides in Ene-Reductases

Capone, Matteo; Dell’Orletta, Gianluca; Nicholls, Bryce T.; Scholes, Gregory D.; Hyster, Todd K.; Aschi, Massimiliano; Daidone, Isabella

doi:10.1021/acscatal.3c03934

Title: Evidence of a Distinctive Enantioselective Binding Mode for the Photoinduced Radical Cyclization of α-Chloroamides in Ene-Reductases

Abstract

We demonstrate here through molecular simulations and mutational studies the origin of the enantioselectivity in the photoinduced radical cyclization of α-chloroacetamides catalyzed by ene-reductases, in particular the Gluconobacter oxidans ene-reductase and the Old Yellow Enzyme 1, which show opposite enantioselectivity. Our results reveal that neither the π-facial selectivity model nor a protein-induced selective stabilization of the transition states is able to explain the enantioselectivity of the radical cyclization in the studied flavoenzymes. We propose a new enantioinduction scenario according to which enantioselectivity is indeed controlled by transition-state stability; however, the relative stability of the prochiral transition states is not determined by direct interaction with the protein but is rather dependent on an inherent degree of freedom within the substrate itself. This intrinsic degree of freedom, distinct from the traditional π-facial exposure mode, can be controlled by the substrate conformational selection upon binding to the enzyme.

Authors:

^[1]; Dell’Orletta, Gianluca ^[1]; Nicholls, Bryce T. ^[2];

^[3]; Hyster, Todd K. ^[2];

^[1];

^[1]

Department of Physical and Chemical Sciences, University of L’Aquila, via Vetoio (Coppito 1), L’Aquila 67010, Italy
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States
Department of Chemistry, Frick Laboratory, Princeton University, Princeton, New Jersey 08544, United States

Publication Date:: Fri Nov 10 00:00:00 EST 2023

Research Org.:: University of L'Aquila (Italy)

Sponsoring Org.:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

OSTI Identifier:: 2205563

Alternate Identifier(s):: OSTI ID: 2228277

Grant/Contract Number:: DESC0019370; SC0019370

Resource Type:: Published Article

Journal Name:: ACS Catalysis

Additional Journal Information:: Journal Name: ACS Catalysis Journal Volume: 13 Journal Issue: 23; Journal ID: ISSN 2155-5435

Publisher:: American Chemical Society

Country of Publication:: United States

Language:: English

Subject:: 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; enantioselectivity; biocatalysis; photocatalysis; asymmetric synthesis; radical cyclization; π-facial

Citation Formats


                    Capone, Matteo, Dell’Orletta, Gianluca, Nicholls, Bryce T., Scholes, Gregory D., Hyster, Todd K., Aschi, Massimiliano, and Daidone, Isabella. Evidence of a Distinctive Enantioselective Binding Mode for the Photoinduced Radical Cyclization of α-Chloroamides in Ene-Reductases.  United States: N. p., 2023. 
Web.  doi:10.1021/acscatal.3c03934.

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                    Capone, Matteo, Dell’Orletta, Gianluca, Nicholls, Bryce T., Scholes, Gregory D., Hyster, Todd K., Aschi, Massimiliano, & Daidone, Isabella. Evidence of a Distinctive Enantioselective Binding Mode for the Photoinduced Radical Cyclization of α-Chloroamides in Ene-Reductases.  United States.  https://doi.org/10.1021/acscatal.3c03934

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                    Capone, Matteo, Dell’Orletta, Gianluca, Nicholls, Bryce T., Scholes, Gregory D., Hyster, Todd K., Aschi, Massimiliano, and Daidone, Isabella. Fri .  
"Evidence of a Distinctive Enantioselective Binding Mode for the Photoinduced Radical Cyclization of α-Chloroamides in Ene-Reductases".  United States.  https://doi.org/10.1021/acscatal.3c03934.

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@article{osti_2205563,

  title        = {Evidence of a Distinctive Enantioselective Binding Mode for the Photoinduced Radical Cyclization of α-Chloroamides in Ene-Reductases},

  author       = {Capone, Matteo and Dell’Orletta, Gianluca and Nicholls, Bryce T. and Scholes, Gregory D. and Hyster, Todd K. and Aschi, Massimiliano and Daidone, Isabella},

  abstractNote = {We demonstrate here through molecular simulations and mutational studies the origin of the enantioselectivity in the photoinduced radical cyclization of α-chloroacetamides catalyzed by ene-reductases, in particular the Gluconobacter oxidans ene-reductase and the Old Yellow Enzyme 1, which show opposite enantioselectivity. Our results reveal that neither the π-facial selectivity model nor a protein-induced selective stabilization of the transition states is able to explain the enantioselectivity of the radical cyclization in the studied flavoenzymes. We propose a new enantioinduction scenario according to which enantioselectivity is indeed controlled by transition-state stability; however, the relative stability of the prochiral transition states is not determined by direct interaction with the protein but is rather dependent on an inherent degree of freedom within the substrate itself. This intrinsic degree of freedom, distinct from the traditional π-facial exposure mode, can be controlled by the substrate conformational selection upon binding to the enzyme.},

  doi          = {10.1021/acscatal.3c03934},

  journal      = {ACS Catalysis},

  number       = 23,

  volume       = 13,

  place        = {United States},

  year         = {Fri Nov 10 00:00:00 EST 2023},

  month        = {Fri Nov 10 00:00:00 EST 2023}

}

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Title: Evidence of a Distinctive Enantioselective Binding Mode for the Photoinduced Radical Cyclization of α-Chloroamides in Ene-Reductases

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Mechanism of Oxygen Evolution and Mn4CaO5 Cluster Restoration in the Natural Water-Oxidizing Catalyst journal, July 2021

Theoretical Insights into the Mechanism and Stereoselectivity of Olefin Cyclopropanation Catalyzed by Two Engineered Cytochrome P450 Enzymes journal, August 2018

Unambiguous Assignment of Reduction Potentials in Diheme Cytochromes journal, July 2014

Some applications of the transition state method to the calculation of reaction velocities, especially in solution journal, January 1935

Directed Evolution Empowered Redesign of Natural Proteins for the Sustainable Production of Chemicals and Pharmaceuticals journal, December 2018

GROMACS: Fast, flexible, and free journal, January 2005

Photoenzymatic Synthesis of α-Tertiary Amines by Engineered Flavin-Dependent “Ene”-Reductases journal, November 2021

The Transformative Power of Biocatalysis in Convergent Synthesis journal, March 2022

Photoenzymatic enantioselective intermolecular radical hydroamination journal, July 2023

Comparison of simple potential functions for simulating liquid water journal, July 1983

New catalytic reactions by enzyme engineering journal, May 2022

Engineering a Non‐Natural Photoenzyme for Improved Photon Efficiency** journal, December 2021

Self‐consistent molecular orbital methods. XX. A basis set for correlated wave functions journal, January 1980

Extending the application of biocatalysis to meet the challenges of drug development journal, November 2018

Inversion of Enantioselectivity of a Mononuclear Non‐Heme Iron(II)‐dependent Hydroxylase by Tuning the Interplay of Metal‐Center Geometry and Protein Structure journal, July 2013

The electron–proton bottleneck of photosynthetic oxygen evolution journal, May 2023

Theoretical characterization of electronic states in interacting chemical systems journal, February 2009

Conformational diversity and enantioconvergence in potato epoxide hydrolase 1 journal, January 2016

CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields journal, January 2009

Engineering the third wave of biocatalysis journal, May 2012

Alternative Fast and Slow Primary Charge‐Separation Pathways in Photosystem II journal, March 2023

Short-Range Electron Transfer in Reduced Flavodoxin: Ultrafast Nonequilibrium Dynamics Coupled with Protein Fluctuations journal, May 2018

Understanding the Mechanistic Requirements for Efficient and Stereoselective Alkene Epoxidation by a Cytochrome P450 Enzyme journal, February 2021

Role of Environmental Dynamic Polarizability in Static Excited State Properties of Embedded Molecular Systems: Application to Disordered Fluorographene Systems journal, December 2022

A climbing image nudged elastic band method for finding saddle points and minimum energy paths journal, December 2000

CHARMM36m: an improved force field for folded and intrinsically disordered proteins journal, November 2016

Laboratory Evolution of Stereoselective Enzymes: A Prolific Source of Catalysts for Asymmetric Reactions journal, August 2010

Engineered P450 Atom-Transfer Radical Cyclases are Bifunctional Biocatalysts: Reaction Mechanism and Origin of Enantioselectivity journal, July 2022

A Molecular Mechanics Model for Flavins journal, August 2019

Enantioselective Radical Processes † journal, August 2003

Methods for Finding Saddle Points and Minimum Energy Paths book, January 2005

PROPKA3: Consistent Treatment of Internal and Surface Residues in Empirical p K a Predictions journal, December 2010

Density‐functional thermochemistry. III. The role of exact exchange journal, April 1993

Statistical Mechanical Modeling of Chemical Reactions in Complex Systems: The Reaction Free Energy Surface journal, September 2004

Combining chemistry and protein engineering for new-to-nature biocatalysis journal, January 2022

Canonical sampling through velocity rescaling journal, January 2007

Alternative Electron-Transfer Channels Ensure Ultrafast Deactivation of Light-Induced Excited States in Riboflavin Binding Protein journal, July 2017

Origins of stereoselectivity in evolved ketoreductases journal, December 2015

LINCS: A linear constraint solver for molecular simulations journal, September 1997

Photoexcitation of flavoenzymes enables a stereoselective radical cyclization journal, June 2019

How the Reorganization Free Energy Affects the Reduction Potential of Structurally Homologous Cytochromes journal, April 2014

Total synthesis of complex terpenoids employing radical cascade processes journal, January 2018

Molecular dynamics with coupling to an external bath journal, October 1984

Software update: The ORCA program system—Version 5.0 journal, March 2022

Old yellow enzyme at 2 Å resolution: overall structure, ligand binding, and comparison with related flavoproteins journal, November 1994

A first-principles method to model perturbed electronic wavefunctions: the effect of an external homogeneous electric field journal, August 2001

The importance of catalytic promiscuity for enzyme design and evolution journal, November 2019

Selective C H bond functionalization with engineered heme proteins: new tools to generate complexity journal, April 2019

Photoenzymatic enantioselective intermolecular radical hydroalkylation journal, June 2020

Density-Functional Theory of the Electronic Structure of Molecules journal, October 1995

Expanding the Enzyme Universe: Accessing Non-Natural Reactions by Mechanism-Guided Directed Evolution journal, February 2015

Quaternary Charge-Transfer Complex Enables Photoenzymatic Intermolecular Hydroalkylation of Olefins journal, December 2020

Mechanism and Dynamics of Photodecarboxylation Catalyzed by Lactate Monooxygenase journal, June 2023

Parametrization of halogen bonds in the CHARMM general force field: Improved treatment of ligand–protein interactions journal, October 2016

A quantitative connection of experimental and simulated folding landscapes by vibrational spectroscopy journal, January 2018

Computational evidence support the hypothesis of neuroglobin also acting as an electron transfer species journal, April 2017

A smooth particle mesh Ewald method journal, November 1995

Asymmetric redox-neutral radical cyclization catalysed by flavin-dependent ‘ene’-reductases journal, December 2019

Substrate control in stereoselective lanthionine biosynthesis journal, November 2014

VMD: Visual molecular dynamics journal, February 1996

Modeling Enzymatic Enantioselectivity using Quantum Chemical Methodology
journal, May 2020

Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals: Miniperspective
journal, October 2014

Engineering new catalytic activities in enzymes
journal, January 2020

Frontiers in Multiscale Modeling of Photoreceptor Proteins
journal, February 2021

AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading
journal, January 2009

Mechanism of Oxygen Evolution and Mn₄CaO₅ Cluster Restoration in the Natural Water-Oxidizing Catalyst
journal, July 2021

Theoretical Insights into the Mechanism and Stereoselectivity of Olefin Cyclopropanation Catalyzed by Two Engineered Cytochrome P450 Enzymes
journal, August 2018

Unambiguous Assignment of Reduction Potentials in Diheme Cytochromes
journal, July 2014

Some applications of the transition state method to the calculation of reaction velocities, especially in solution
journal, January 1935

Directed Evolution Empowered Redesign of Natural Proteins for the Sustainable Production of Chemicals and Pharmaceuticals
journal, December 2018

GROMACS: Fast, flexible, and free
journal, January 2005

Photoenzymatic Synthesis of α-Tertiary Amines by Engineered Flavin-Dependent “Ene”-Reductases
journal, November 2021

The Transformative Power of Biocatalysis in Convergent Synthesis
journal, March 2022

Photoenzymatic enantioselective intermolecular radical hydroamination
journal, July 2023

Comparison of simple potential functions for simulating liquid water
journal, July 1983

New catalytic reactions by enzyme engineering
journal, May 2022

Engineering a Non‐Natural Photoenzyme for Improved Photon Efficiency**
journal, December 2021

Self‐consistent molecular orbital methods. XX. A basis set for correlated wave functions
journal, January 1980

Extending the application of biocatalysis to meet the challenges of drug development
journal, November 2018

Inversion of Enantioselectivity of a Mononuclear Non‐Heme Iron(II)‐dependent Hydroxylase by Tuning the Interplay of Metal‐Center Geometry and Protein Structure
journal, July 2013

The electron–proton bottleneck of photosynthetic oxygen evolution
journal, May 2023

Theoretical characterization of electronic states in interacting chemical systems
journal, February 2009

Conformational diversity and enantioconvergence in potato epoxide hydrolase 1
journal, January 2016

CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields
journal, January 2009

Engineering the third wave of biocatalysis
journal, May 2012

Alternative Fast and Slow Primary Charge‐Separation Pathways in Photosystem II
journal, March 2023

Short-Range Electron Transfer in Reduced Flavodoxin: Ultrafast Nonequilibrium Dynamics Coupled with Protein Fluctuations
journal, May 2018

Understanding the Mechanistic Requirements for Efficient and Stereoselective Alkene Epoxidation by a Cytochrome P450 Enzyme
journal, February 2021

Role of Environmental Dynamic Polarizability in Static Excited State Properties of Embedded Molecular Systems: Application to Disordered Fluorographene Systems
journal, December 2022

A climbing image nudged elastic band method for finding saddle points and minimum energy paths
journal, December 2000

CHARMM36m: an improved force field for folded and intrinsically disordered proteins
journal, November 2016

Laboratory Evolution of Stereoselective Enzymes: A Prolific Source of Catalysts for Asymmetric Reactions
journal, August 2010

Engineered P450 Atom-Transfer Radical Cyclases are Bifunctional Biocatalysts: Reaction Mechanism and Origin of Enantioselectivity
journal, July 2022

A Molecular Mechanics Model for Flavins
journal, August 2019

Enantioselective Radical Processes ^†
journal, August 2003

Methods for Finding Saddle Points and Minimum Energy Paths
book, January 2005

PROPKA3: Consistent Treatment of Internal and Surface Residues in Empirical p K _a Predictions
journal, December 2010

Density‐functional thermochemistry. III. The role of exact exchange
journal, April 1993

Statistical Mechanical Modeling of Chemical Reactions in Complex Systems: The Reaction Free Energy Surface
journal, September 2004

Combining chemistry and protein engineering for new-to-nature biocatalysis
journal, January 2022

Canonical sampling through velocity rescaling
journal, January 2007

Alternative Electron-Transfer Channels Ensure Ultrafast Deactivation of Light-Induced Excited States in Riboflavin Binding Protein
journal, July 2017

Origins of stereoselectivity in evolved ketoreductases
journal, December 2015

LINCS: A linear constraint solver for molecular simulations
journal, September 1997

Photoexcitation of flavoenzymes enables a stereoselective radical cyclization
journal, June 2019

How the Reorganization Free Energy Affects the Reduction Potential of Structurally Homologous Cytochromes
journal, April 2014

Total synthesis of complex terpenoids employing radical cascade processes
journal, January 2018

Molecular dynamics with coupling to an external bath
journal, October 1984

Software update: The ORCA program system—Version 5.0
journal, March 2022

Old yellow enzyme at 2 Å resolution: overall structure, ligand binding, and comparison with related flavoproteins
journal, November 1994

A first-principles method to model perturbed electronic wavefunctions: the effect of an external homogeneous electric field
journal, August 2001

The importance of catalytic promiscuity for enzyme design and evolution
journal, November 2019

Selective C H bond functionalization with engineered heme proteins: new tools to generate complexity
journal, April 2019

Photoenzymatic enantioselective intermolecular radical hydroalkylation
journal, June 2020

Density-Functional Theory of the Electronic Structure of Molecules
journal, October 1995

Expanding the Enzyme Universe: Accessing Non-Natural Reactions by Mechanism-Guided Directed Evolution
journal, February 2015

Quaternary Charge-Transfer Complex Enables Photoenzymatic Intermolecular Hydroalkylation of Olefins
journal, December 2020

Mechanism and Dynamics of Photodecarboxylation Catalyzed by Lactate Monooxygenase
journal, June 2023

Parametrization of halogen bonds in the CHARMM general force field: Improved treatment of ligand–protein interactions
journal, October 2016

A quantitative connection of experimental and simulated folding landscapes by vibrational spectroscopy
journal, January 2018

Computational evidence support the hypothesis of neuroglobin also acting as an electron transfer species
journal, April 2017

A smooth particle mesh Ewald method
journal, November 1995

Asymmetric redox-neutral radical cyclization catalysed by flavin-dependent ‘ene’-reductases
journal, December 2019

Substrate control in stereoselective lanthionine biosynthesis
journal, November 2014

VMD: Visual molecular dynamics
journal, February 1996