# Molecular Origins of Simultaneous Chemo‑, Enantio‑, and Substrate Selectivity in Non-Natural Photoenzymatic Radical Reactions

## TL;DR

This paper explains how a special enzyme can control three types of chemical selectivity in radical reactions through a newly discovered preactivation step and electronic state interactions.

## Contribution

The study reveals a new preactivation mechanism and electronic state dynamics that enable triple selectivity in photoenzymatic reactions.

## Key findings

- Triple selectivity in photoenzymatic reactions is governed by reaction-level mechanisms, not binding preferences.
- A previously unknown preactivation step involving bond elongation is essential for productive photochemistry.
- Chemoselectivity is controlled by conical intersection dynamics between electronic states.

## Abstract

Selective radical
chemistry poses fundamental challenges for modern
catalysis. Non-natural photoenzymes, most prominently flavin-dependent
“ene”-reductases, have recently emerged as appealing
systems to address these challenges by offering unmatched control
over chemo-, enantio-, and substrate selectivity, yet their underlying
photocatalytic mechanisms remain unclear. Here, we reveal the complete
molecular basis of the triple selectivity control in the photoenzymatic
radical reactions by the flavin-dependent “ene”-reductase GkOYE-G7 through computational simulations based on multiscale
multireference-quantum-mechanics/molecular-mechanics modeling and
bias-exchange metadynamics. Our findings demonstrate that control
emerges from reaction-level mechanisms rather than binding preferences.
We discover that productive photochemistry requires a previously unknown
preactivation step involving bond elongation. Stereochemical outcomes
likely result from reaction barrier differences, while chemoselectivity,
is controlled by crossing points between the ground and excited electronic
states around the conical intersection that channel the reaction before
competing pathways activate. Substrate scope follows predictable electronic-steric
rules, establishing fundamental principles for engineering next-generation
photoenzymes with predictable selectivity profiles.