title: Covalent docking predicts substrates for haloalkanoate dehalogenase superfamily phosphatases.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Chemistry, and §Department of Bioengineering and Therapeutic Sciences, University of California San Francisco , San Francisco, California 94158, United States.
authors.forename: Nir
authors.initials: N
authors.lastname: London
authors.forename: Jeremiah D
authors.initials: JD
authors.lastname: Farelli
authors.forename: Shoshana D
authors.initials: SD
authors.lastname: Brown
authors.forename: Chunliang
authors.initials: C
authors.lastname: Liu
authors.forename: Hua
authors.initials: H
authors.lastname: Huang
authors.forename: Magdalena
authors.initials: M
authors.lastname: Korczynska
authors.forename: Nawar F
authors.initials: NF
authors.lastname: Al-Obaidi
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Babbitt
authors.forename: Steven C
authors.initials: SC
authors.lastname: Almo
authors.forename: Karen N
authors.initials: KN
authors.lastname: Allen
authors.forename: Brian K
authors.initials: BK
authors.lastname: Shoichet
mesh_terms: D000818:Animals; D030562:Databases, Protein; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D008024:Ligands; D010744:Phosphoric Monoester Hydrolases