The change in Gibbs free energy regulates topoisomerase-IB activity: a molecular dynamics and MM/GBSA study

The human topoisomerase-IB enzyme relieves DNA torsional stress in biological cells by transiently breaking one strands of DNA. Their role is vital for cellular processes during central dogma. By attacking the DNA's phosphodiester bond nucleophilically, the active tyrosine of topoisomerase-IB causes a break in one strand of DNA and creates an intermediate phosphorylated tyrosine (PTR) bond at the 3' of the DNA strands. After this, by controlled rotation of its uncut DNA strands, the enzyme does its enzymatic activity. Although there are various biophysical and biochemical studies have examined this catalytic activity, fundamental questions remain, how does the Gibbs free energy facilitate topoisomerase activity of Topo-IB enzyme? We have used computational simulation methods as 600 ns molecular dynamics simulations and MM/GBSA, to explain the structural mechanisms underlying Topo-IB activity. Here, we have found the Gibbs free energy of certain enzyme amino acid plays an essential role in generating polar solvation energy, which is vital for stabilizing the enzyme's activity. A detailed study of the major role of Lys-318 in the controlled rotation mechanism suggests that the processing DNA cooperates with the enzymes for large conformational changes. These findings will guide future cellular processes studies of type-IB enzymes and their antidrug.