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PER1 and PER2 are among the class A β-lactamase enzymes, which have evolved clinically to form antibiotic resistance and have significantly expanded their spectrum of activity. Hence, there is a need to study the clinical mutation responsible for such β-lactamase mediated antibiotic resistance. Alterations in catalytic centre and Ω-loop structure could be the cause of antibiotic resistance in these β-lactamase enzymes. Structural and functional alterations are caused due to mutations on or near the catalytic centre, which results in active site plasticity and are responsible for its expanded spectrum of activity in these class A β-lactamase enzymes. Multiple sequence alignment, structure, kinetic, molecular docking, MMGBSA and molecular dynamic simulation comparisons were done on 38 clinically mutated and wild class A β-lactamase enzymes. This work shows that PER1 and PER2 enzymes contains most unique mutations and have altered Ω-loop structure, which could be responsible for altering the structure-activity relationship and extending the spectrum of activity of these enzymes. Alterations in molecular docking, MMGBSA, kinetic values reveals the modification in the binding and activity of these clinically mutated enzymes with antibiotics. Further, the cause of these alterations can be revealed by active site interactions and H-bonding pattern of these enzymes with antibiotics. Met69Gln, Glu104Thr, Tyr105Trp, Met129His, Pro167Ala, Glu168Gln, Asn170His, Ile173Asp and Asp176Gln mutations were uniquely found in PER1 and PER2 enzymes. These mutations occurs at catalytic important residues and results in altered interactions with β-lactam antibiotics. Hence, these mutations could be responsible for altering the structure-activity of PER1 and PER2 enzymes. Communicated by Ramaswamy H. Sarma

Insights into structure and activity relationship of clinically mutated PER1 and PER2 class A β-lactamase enzymes