title: Conformational diversity of bacterial FabH: implications for molecular recognition specificity.
abstract: The molecular basis of variable substrate and inhibitor specificity of the highly conserved bacterial fatty acid synthase enzyme, FabH, across different bacterial species remains poorly understood. In the current work, we explored the conformational diversity of FabH enzymes to understand the determinants of diverse interaction specificity across Gram-positive and Gram-negative bacteria. Atomistic molecular dynamics simulations reveal that FabH from E. coli and E. faecalis exhibit distinct native state conformational ensembles and dynamic behaviors. Despite strikingly similar substrate binding pockets, hot spot assessment using computational solvent mapping identified quite different favorable binding interactions between the two homologs. Our data suggest that FabH utilizes protein dynamics and seemingly minor sequence and structural differences to modulate its molecular recognition and substrate specificity across bacterial species. These insights will potentially facilitate the rational design and development of antibacterial inhibitors against FabH enzymes.
authors.affiliation: Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, 900 S. Ashland Ave-m/c 870, Chicago, IL 60607-7173, USA.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Mittal
authors.affiliation: Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, 900 S. Ashland Ave-m/c 870, Chicago, IL 60607-7173, USA. Electronic address: mjohnson@uic.edu.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Johnson
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; D000123:Acetyltransferases / Q000737:chemistry*; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry*; D001665:Binding Sites; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D013293:Enterococcus faecalis / Q000378:metabolism*; D004926:Escherichia coli / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000737:chemistry*; D054889:Fatty Acid Synthase, Type II / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D011487:Protein Conformation; D040681:Structural Homology, Protein; D013816:Thermodynamics
chemical_list: D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D008024:Ligands; D000123:Acetyltransferases; C557158:fabH protein, E coli; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; D054889:Fatty Acid Synthase, Type II
keywords: Binding specificity; Computational solvent mapping; Conformational diversity; FabH