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Covalent docking predicts substrates for haloalkanoate dehalogenase superfamily phosphatases

London N, Farelli JD, Brown SD, Liu C, Huang H, Korczynska M, Al-Obaidi NF, Babbitt PC, Almo SC, Allen KN, Shoichet BK (2014) Biochemistry, 54, 528-537. PMCID: PMC4303301

The Computational Core demonstrates the utility of their novel covalent docking strategy while capitalizing on the enzymatic expertise of the HAD Bridging Project. Covalent docking, with corroboration from genome neighborhood network analysis, allowed the group to finally idenitify the HAD superfamily member responsible for performing an "orphan" reaction in Bacteroides riboflavin biosynthesis.


Enzyme function prediction remains an important open problem. Though structure-based modeling, such as metabolite docking, can identify substrates of some enzymes, it is ill-suited to reactions that progress through a covalent intermediate. Here we investigated the ability of covalent docking to identify substrates that pass through such a covalent intermediate, focusing particularly on the haloalkanoate dehalogenase superfamily. In retrospective assessments, covalent docking recapitulated substrate binding modes of known cocrystal structures and identified experimental substrates from a set of putative phosphorylated metabolites. In comparison, noncovalent docking of high-energy intermediates yielded nonproductive poses. In prospective predictions against seven enzymes, a substrate was identified for five. For one of those cases, a covalent docking prediction, confirmed by empirical screening, and combined with genomic context analysis, suggested the identity of the enzyme that catalyzes the orphan phosphatase reaction in the riboflavin biosynthetic pathway of Bacteroides.

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Abstract Image

Figure 1: Overview of covalent docking to the HADSF. An illustration of the sampling in the HADSF covalent docking.

Figure 2: Substrate pose recovery by covalent docking. Examples of covalent docking pose predictions (magenta) for known HAD (white)/substrate (yellow) complexes.

Figure 3: EFI-501083 (UniProt: Q8A947) may be the missing enzyme for the orphan reaction in the riboflavin biosynthetic pathway.

Reprinted with permission from London et al. Biochemistry 54, 528-537. Copyright 2014 American Chemical Society.