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Accurate prediction by AlphaFold2 for ligand binding in a reductive dehalogenase and implications for PFAS (per-and polyfluoroalkyl substance) biodegradation

Guo, Hao-Bo, Varaljay, Vanessa A., Kedziora, Gary, Taylor, Kimberly, Farajollahi, Sanaz, Lombardo, Nina, Harper, Eric, Hung, Chia, Gross, Marie, Perminov, Alexander, Dennis, Patrick, Kelley-Loughnane, Nancy, Berry, Rajiv·2023·Scientific Reports
DOI 10.1038/s41598-023-30310-xPMC PMC10008544

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Abstract

Despite the success of AlphaFold2 (AF2), it is unclear how AF2 models accommodate for ligand binding. Here, we start with a protein sequence from Acidimicrobiaceae TMED77 (T7RdhA) with potential for catalyzing the degradation of per- and polyfluoroalkyl substances (PFASs). AF2 models and experiments identified T7RdhA as a corrinoid iron-sulfur protein (CoFeSP) which uses a norpseudo-cobalamin (BVQ) cofactor and two Fe 4 S 4 iron-sulfur clusters for catalysis. Docking and molecular dynamics simulations suggest that T7RdhA uses perfluorooctanoic acetate (PFOA) as a substrate, supporting the reported defluorination activity of its homolog, A6RdhA. We showed that AF2 provides processual (dynamic) predictions for the binding pockets of ligands (cofactors and/or substrates). Because the pLDDT scores provided by AF2 reflect the protein native states in complex with ligands as the evolutionary constraints, the Evoformer network of AF2 predicts protein structures and residue flexibility in complex with the ligands, i.e., in their native states. Therefore, an apo-protein predicted by AF2 is actually a holo-protein awaiting ligands.

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Metadata

Authors
Guo, H.-B., Varaljay, V. A., Kedziora, G., Taylor, K., Farajollahi, S., Lombardo, N., Harper, E., Hung, C., Gross, M., Perminov, A., Dennis, P., Kelley-Loughnane, N., & Berry, R.
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2023-03-11
Volume
13
Issue
1
ISSN
2045-2322
DOI
10.1038/s41598-023-30310-x
PMC
PMC10008544
Cited by
22
References
10
Language
en
Licence
Funders
OUSD (R&E) ARAP Program

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