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

Hao-Bo Guo, Vanessa Varaljay, Gary Kedziora, Kimberly Taylor, Sanaz Farajollahi, Nina Lombardo, Eric Harper, Chia Hung, Marie Gross, Alexander Perminov,
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Published: 20 September 2022
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 [4Fe4S] iron-sulfur clusters (SF4) 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.
Keywords: protein / AF2 / models / binding / sulfur / native / substrates / iron / AlphaFold2 / structures

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