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Computational insights into pH‐dependence of structure and dynamics of pyrazinamidase: A comparison of wild type and mutants
Author(s) -
Esmaeeli Reza,
Mehrnejad Faramarz,
MirDerikvand Mohammad,
Gopalpoor Niloofar
Publication year - 2019
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.27543
Subject(s) - mutant , molecular dynamics , enzyme , point mutation , protonation , chemistry , biophysics , active site , wild type , pyrazinamide , mutation , biochemistry , stereochemistry , computational chemistry , biology , organic chemistry , gene , ion , rifampicin , antibiotics
The mycobacterial enzyme pyrazinamidase (PZase) is the target of key tuberculosis drug, pyrazinamide. Mutations in PZase cause drug resistance. Herein, three point mutations, W68G, L85P, and V155G, were investigated through over 8 µs of molecular dynamics simulations coupled with essential dynamics and binding pocket analysis at neutral (pH = 7) and acidic (pH = 4) ambient conditions. The 51‐71 flap region exhibited drastic displacement leading to enlargement of binding cavity, especially at the lower pH. Accessibility of solvent to the active site of the mutant enzymes was also reduced. The protonation of key surface residues at low pH results in more contribution of these residues to structural stability and integrity of the enzyme and reduced interactions with solvent molecules, which acts as a cage, keeping the enzyme together. The observed results suggest a pattern of structural alterations due to point mutations in PZase, which is consistent with other experimental and theoretical investigations and, can be harnessed for drug design purposes.