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Delineating the Role of mutation on the structural stability and conformational landscape of inhibitor-resistant TEMβ-lactamase: A high-performance molecular dynamics simulations Study
  • Sandip Mukherjee,
  • Mandira Mukherjee,
  • Padmaja Mishra
Sandip Mukherjee
Calcutta School of Tropical Medicine
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Mandira Mukherjee
Calcutta School of Tropical Medicine
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Padmaja Mishra
Saha Institute of Nuclear Physics

Corresponding Author:[email protected]

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The gain of function mutations and structural adjustment towards β-lactamase inhibitors in TEM-type β-lactamase among the uropathogenic E.coli (UPEC) culminates into treatment complications and demands a detailed investigation. In this study, uncharacterized amino acid substitutions, M69L/I84V/W165G/V184A/V262I/N276S in inhibitor-resistant TEM (IRT) β-lactamase isolated from clinical UPEC were subjected to extensive molecular dynamics (EMD) simulations for 100 ns to estimate the parameters such as RMSD, RMSF, the radius of gyration (Rg), Contour plot (Rg/RMSD) and secondary structure element (SSE), etc. Residue interaction networks, principal component analysis (PCA), and correlation heatmaps were generated to predict the relation between functionally important atomic motions to uncover the structural stability of the mutants. To avoid the false positive conclusion of the simulation study, we have performed three identically parameterize replicas of 100ns each. Alterations in hydrophobic interactions resulted in conformation changes exhibited as comparable residue interaction networks. Besides, PCA and porcupine plot analysis based on the ensemble of structure from molecular dynamics trajectories revealed the collective atomic motions of the IRT variants that impart structural flexibility of their active site loop. Therefore, this is the first study of its kind conducted on IRT mutants that delineate intricate protein motions that contribute to their stability and folding using high-performance protein dynamics which is an absolute necessity to design candidate molecules because of the clinical threat of emerging resistance against potent β-lactam antibiotics.