Alexey Aleksandrov
CNRS, Laboratoire d’Optique et Biosciences, Ecole Polytechnique, Institut polytechnique de Paris, F-91128 Palaiseau, France
Molecular Simulation and Experimental Insights into the Catalytic Mechanism of Fatty Acid Photodecarboxylase
Abstract
Fatty acid photodecarboxylase (FAP) is a recently discovered photoenzyme that converts fatty acids into hydrocarbons through a light-driven radical mechanism. In this talk, I will show how we combine molecular dynamics (MD) and quantum mechanics/molecular mechanics simulations with time-resolved spectroscopic observations to elucidate key mechanistic aspects of FAP function. MD simulations reveal a strong dependence of active-site organization on substrate chain length, with short-chain substrates inducing tighter pocket packing aided by the alkane product acting as a co-catalyst, thereby explaining the unexpectedly high activity toward medium-chain fatty acids. In contrast, substrate-free simulations show expansion of the flavin-binding pocket and increased water penetration, rationalizing ultrafast spectroscopic evidence for hydrated electron formation following photoexcitation of the flavin anion radical. Combined experimental and simulation results further reveal details of the FAP photocycle, including transformation of the CO₂ coproduct into bicarbonate at cryogenic temperatures, while this pathway is suppressed under physiological conditions, explaining the strong temperature dependence observed experimentally. Overall, by integrating simulations with spectroscopy, we demonstrate how protein dynamics and active-site electrostatics govern light-driven radical chemistry in FAP.
References
Bonvalet et al, Dynamics and Catalytic Conversion of the CO2 Coproduct in Fatty Acid Photodecarboxylase. ACS Catalysis 2025.
Samire et al, Autocatalytic effect boosts the production of medium-chain hydrocarbons by fatty acid photodecarboxylase. Science Advances 2023, 9 (13), eadg3881.
Vos et al, Ultrafast photooxidation of semireduced flavin in fatty acid photodecarboxylase. Science Advances 2025, 11 (38), eadz1904.
