title: Ligand-induced structural changes in TEM-1 probed by molecular dynamics and relative binding free energy calculations.
abstract: The TEM family of enzymes has had a crucial impact on the pharmaceutical industry due to their important role in antibiotic resistance. Even with the latest technologies in structural biology and genomics, no 3D structure of a TEM-1/antibiotic complex is known previous to acylation. Therefore, the comprehension of their capability in acylate antibiotics is based on the protein macromolecular structure uncomplexed. In this work, molecular docking, molecular dynamic simulations, and relative free energy calculations were applied in order to get a comprehensive and thorough analysis of TEM-1/ampicillin and TEM-1/amoxicillin complexes. We described the complexes and analyzed the effect of ligand binding on the overall structure. We clearly demonstrate that the key residues involved in the stability of the ligand (hot-spots) vary with the nature of the ligand. Structural effects such as (i) the distances between interfacial residues (Ser70-Oγ and Lys73-Nζ, Lys73-Nζ and Ser130-Oγ, and Ser70-Oγ-Ser130-Oγ), (ii) side chain rotamer variation (Tyr105 and Glu240), and (iii) the presence of conserved waters can be also influenced by ligand binding. This study supports the hypothesis that TEM-1 suffers structural modifications upon ligand binding.
authors.affiliation: REQUIMTE/Departamento de Química, Faculdade de Ciências da Universidade do Porto , Rua do Campo Alegre s/n, 4169-007 Porto, Portugal.
authors.forename: A C
authors.initials: AC
authors.lastname: Pimenta
authors.forename: J M
authors.initials: JM
authors.lastname: Martins
authors.forename: R
authors.initials: R
authors.lastname: Fernandes
authors.forename: I S
authors.initials: IS
authors.lastname: Moreira
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000658:Amoxicillin / Q000737:chemistry*; D000667:Ampicillin / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D001665:Binding Sites; D006090:Gram-Negative Bacteria / Q000737:chemistry / Q000201:enzymology; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D013816:Thermodynamics; D014867:Water / Q000737:chemistry; D018440:beta-Lactam Resistance; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D000900:Anti-Bacterial Agents; D008024:Ligands; D065093:beta-Lactamase Inhibitors; D014867:Water; D000667:Ampicillin; D000658:Amoxicillin; D001618:beta-Lactamases; C034413:beta-lactamase TEM-1