title: Molecular dynamics investigations of BioH protein substrate specificity for biotin synthesis.
abstract: BioH, an enzyme of biotin synthesis, plays an important role in fatty acid synthesis which assembles the pimelate moiety. Pimeloyl-acyl carrier protein (ACP) methyl ester, which is long known to be a biotin precursor, is the physiological substrate of BioH. Azelayl methyl ester, which has a longer chain than pimeloyl methyl ester, conjugated to ACP is also indeed accepted by BioH with very low rate of hydrolysis. To date, the substrate specificity for BioH and the molecular origin for the experimentally observed rate changes of hydrolysis by the chain elongation have remained elusive. To this end, we have investigated chain elongation effects on the structures by using the fully atomistic molecular dynamics simulations combined with binding free energy calculations. The results indicate that the substrate specificity is determined by BioH together with ACP. The added two methylenes would increase the structural flexibility by protein motions at the interface of ACP and BioH, instead of making steric clashes with the side chains of the BioH hydrophobic cavity. On the other hand, the slower hydrolysis of azelayl substrate is suggested to be associated with the loose of contacts between BioH and ACP, and with the lost electrostatic interactions of two ionic/hydrogen bonding networks at the interface of the two proteins. The present study provides important insights into the structure-function relationships of the complex of BioH with pimeloyl-ACP methyl ester, which could contribute to further understanding about the mechanism of the biotin synthetic pathway, including the catalytic role of BioH.
authors.affiliation: a State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences , Chinese Academy of Sciences , Beijing 100000 , P.R. China.|b Institute of Theoretical Chemistry , Jilin University , Changchun 130023 , P.R. China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Xue
authors.affiliation: b Institute of Theoretical Chemistry , Jilin University , Changchun 130023 , P.R. China.
authors.forename: Ying-Lu
authors.initials: YL
authors.lastname: Cui
authors.affiliation: b Institute of Theoretical Chemistry , Jilin University , Changchun 130023 , P.R. China.
authors.forename: Qing-Chuan
authors.initials: QC
authors.lastname: Zheng
authors.affiliation: b Institute of Theoretical Chemistry , Jilin University , Changchun 130023 , P.R. China.
authors.forename: Hong-Xing
authors.initials: HX
authors.lastname: Zhang
mesh_terms: D000213:Acyl Carrier Protein / Q000737:chemistry / Q000378:metabolism; D001710:Biotin / Q000096:biosynthesis / Q000737:chemistry*; D002384:Catalysis; D004798:Enzymes / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D013379:Substrate Specificity
chemical_list: D000213:Acyl Carrier Protein; D004798:Enzymes; D001710:Biotin
keywords: BioH substrate specificity; MM-GBSA; biotin synthetic pathway; molecular dynamics simulation