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Multiscale analysis of enantioselectivity in enzyme-catalysed 'lethal synthesis' using projector-based embedding
Xinglong Zhang1, Simon J Bennie2, Marc W van der Kamp2,3
1Physical and Theoretical Chemistry Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QZ, UK.
Royal Society Open Science
|March 9, 2018
Summary
This study shows how a projection-based embedding method accurately predicts the enantioselectivity of enzyme reactions, like the lethal synthesis of pesticides by citrate synthase. This computational approach offers a reliable way to determine stereoselectivity in enzymatic systems.
Area of Science:
- Biochemistry
- Computational Chemistry
- Enzymology
Background:
- Fluoroacetate pesticide action relies on 'lethal synthesis' of fluorocitrate.
- Citrate synthase catalyzes this synthesis via enantioselective enolization of fluoroacetyl-coenzyme A.
Purpose of the Study:
- To apply a projection-based embedding method for calculating enzyme reaction profiles.
- To determine the stereoselectivity of the citrate synthase reaction using advanced computational methods.
Main Methods:
- Utilized quantum mechanics/molecular mechanics (QM/MM) for pathway optimization.
- Employed a projection-based embedding method to calculate coupled cluster (CCSD(T)) reaction profiles.
- Compared pro-R and pro-S proton abstraction at the CCSD(T)-in-DFT//MM level.
Main Results:
- The method correctly predicted the enantioselectivity of citrate synthase.
- Demonstrated the potential of projection-based embedding for determining enzymatic stereoselectivity.
- Showcased the method's simplicity and ability to eliminate density functional theory (DFT) functional variability.
Conclusions:
- Projection-based embedding is effective for calculating high-accuracy enzyme reaction barriers.
- This approach enables efficient and reliable determination of stereoselectivity in enzymatic systems.
- The method provides CCSD(T) quality results for enzyme reaction barriers, reducing computational cost.