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However, as enthalpic and entropic contributions are coupled to each other and even tiny conformational changes could bring in noticeable free energy changes, a quantitative description is essential to understand the contribution of pure dynamic allostery. In recent years, many “quasi”-dynamic allosteric proteins have been found to only experience subtle conformational changes during allosteric regulation. These secondary non-catalytically-active loops offer attractive targets for novel noncompetitive inhibitors of TEM beta-lactamase.ĭynamic allostery refers to one important class of allosteric regulation that does not involve noticeable conformational changes upon effector binding. The results suggest that the H10-H11 loop (residues 214-221) is a secondary anchor for larger extended spectrum ligands, while the H9-H10 loop (residues 194-202) is distal from the active site and stabilizes the protein against structural changes. Mechanisms for substrate recognition are elucidated using multivariate comparative analysis of molecular dynamics trajectories to identify changes in dynamics resulting from point mutations and ligand binding, and the conserved dynamics, which are functionally important, are extracted as well.
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An allosteric mechanism known to inhibit enzymatic function in TEM beta-lactamase is identified, along with other allosteric binding targets. Dynamic allostery is predicted based on a quasi-harmonic normal mode analysis using a perturbation scan. Comparisons are made between wild-type TEM-1 and TEM-2 and the extended-spectrum mutants TEM-10 and TEM-52, both in apo form and in complex with four different antibiotics (ampicillin, amoxicillin, cefotaxime and ceftazidime). Here, the functional dynamics that control substrate recognition in TEM beta-lactamase are investigated using all-atom molecular dynamics simulations. Recently, extended-spectrum and inhibitor-resistant mutants have become a global health problem. The beta-lactamase enzyme provides effective resistance to beta-lactam antibiotics due to substrate recognition controlled by point mutations.