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Advisor(s)
Abstract(s)
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.