A Distributed Diffusion Landscape Governs CO2 Coproduct Release from Fatty Acid Photodecarboxylase
- 1Department of Physical and Chemical Sciences, University of L’Aquila, via Vetoio (Coppito 1), L'Aquila, Italy, 67100
Abstract
The diffusion of small ligands within proteins is a fundamental yet poorly resolved step in enzymatic turnover.Recent studies have shown that ligand migration can involve networks of transient internal cavities and multiple competing exit routes, raising the question of whether such heterogeneity is a general feature of small-molecule egress.Here, we address this question in fatty acid photodecarboxylase (FAP), a light-driven enzyme that generates CO 2 as a small diffusive coproduct during fatty-acid decarboxylation.Using nine independent classical molecular dynamics simulations of Cv FAP, we show that CO 2 escapes the protein on the µs timescale with kinetics consistent with time-resolved infrared measurements, whereas the alkane product remains bound on the simulated timescale.Before release, CO 2 diffuses through a heterogeneous network of transient cavities, populating several distinct sites before escaping through multiple competing surface exit pathways rather than a single dominant route.One cavity positions CO 2 near C432, consistent with formation of the thiocarbonate intermediate previously identified.CO 2 release is likewise distributed among multiple surface exit points, none corresponding to the water channel observed in the dark-state enzyme.These findings reveal that CO 2 clearance in FAP occurs through an intrinsically heterogeneous diffusion landscape. SignificanceProtein function often depends on the ability of small molecules to move through the protein, but how these molecules find their way out of buried active sites remains poorly understood.Using molecular dynamics simulations of fatty acid photodecarboxylase, we show that CO 2 egress is not governed by a single structural pathway.Instead, CO 2 migrates through a dynamic network of transient cavities and escapes through multiple competing surface routes.The resulting release kinetics are consistent with experimental measurements, linking the heterogeneous diffusion landscape to the observed timescale of CO 2 release.Our findings highlight how protein conformational dynamics can create distributed and multiroute pathways for small-molecule transport, providing an atomistic framework for understanding product egress from enzymes.
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BibTeX
@misc{dellorletta2026distributed,
title = {{A Distributed Diffusion Landscape Governs CO2 Coproduct Release from Fatty Acid Photodecarboxylase}},
author = {Gianluca Dell'Orletta and Isabella Daidone},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15008533/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008533/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - A Distributed Diffusion Landscape Governs CO2 Coproduct Release from Fatty Acid Photodecarboxylase
AU - Gianluca Dell'Orletta
AU - Isabella Daidone
PY - 2026
DA - 2026/09/09
PB - ChemRxiv
DO - 10.26434/chemrxiv.15008533/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008533/v1
AB - The diffusion of small ligands within proteins is a fundamental yet poorly resolved step in enzymatic turnover.Recent studies have shown that ligand migration can involve networks of transient internal cavities and multiple competing exit routes, raising the question of whether such heterogeneity is a general feature of small-molecule egress.Here, we address this question in fatty acid photodecarboxylase (FAP), a light-driven enzyme that generates CO 2 as a small diffusive coproduct during fatty-acid decarboxylation.Using nine independent classical molecular dynamics simulations of Cv FAP, we show that CO 2 escapes the protein on the µs timescale with kinetics consistent with time-resolved infrared measurements, whereas the alkane product remains bound on the simulated timescale.Before release, CO 2 diffuses through a heterogeneous network of transient cavities, populating several distinct sites before escaping through multiple competing surface exit pathways rather than a single dominant route.One cavity positions CO 2 near C432, consistent with formation of the thiocarbonate intermediate previously identified.CO 2 release is likewise distributed among multiple surface exit points, none corresponding to the water channel observed in the dark-state enzyme.These findings reveal that CO 2 clearance in FAP occurs through an intrinsically heterogeneous diffusion landscape. SignificanceProtein function often depends on the ability of small molecules to move through the protein, but how these molecules find their way out of buried active sites remains poorly understood.Using molecular dynamics simulations of fatty acid photodecarboxylase, we show that CO 2 egress is not governed by a single structural pathway.Instead, CO 2 migrates through a dynamic network of transient cavities and escapes through multiple competing surface routes.The resulting release kinetics are consistent with experimental measurements, linking the heterogeneous diffusion landscape to the observed timescale of CO 2 release.Our findings highlight how protein conformational dynamics can create distributed and multiroute pathways for small-molecule transport, providing an atomistic framework for understanding product egress from enzymes.
ER -