Water network chemistry to exploit the nature of catalytic water molecules in Mtb DNA gyrase: a computational study to understand the binding mechanism of fluoroquinolones.

The dynamics of DNA gyrase and mutants of DNA gyrA such as G88A, A90V, S91P, D94A, D94G, D94N, D94Y; and double-point mutant (S91P-D94G), are meticulously investigated using computational approaches. Molecular dynamics (MD) and hydration thermodynamics have shed light on the fundamental, mechanistic basis of mutations on the conformational stability of Quinolone Binding Pocket (QBP) of DNA gyrase. Analysis of MD results revealed the displacement of a single crystal water molecule (HOH201) from the catalytic site of wild-type (WT) and mutants of DNA gyrA. This prompted our research group to probe the five crystal water molecules present in the QBP of the enzyme using water thermodynamics. Hydration thermodynamics analysis revealed the displacement of HOH201 due to unstable thermodynamic signatures. Further, the analysis highlighted significant changes in thermodynamic signatures and locations of five crystal water hydration sites upon mutation. Integrated MD simulations and water thermodynamics provided promising insights into the conformational changes and inaccessibility of the catalytic water molecule that can influence the design of DNA gyrase inhibitors.Communicated by Ramaswamy H. Sarma.