Role of the protein in the DNA sequence specificity of the cleavage site stabilized by the camptothecin topoisomerase IB inhibitor: a metadynamics study.

ABSTRACT: Camptothecin (CPT) is a topoisomerase IB (TopIB) selective inhibitor whose derivatives are currently used in cancer therapy. TopIB cleaves DNA at any sequence, but in the presence of CPT the only stabilized protein-DNA covalent complex is the one having a thymine in position -1 with respect to the cleavage site. A metadynamics simulation of two TopIB-DNA-CPT ternary complexes differing for the presence of a thymine or a cytosine in position -1 indicates the occurrence of two different drug's unbinding pathways. The free-energy difference between the bound state and the transition state is large when a thymine is present in position -1 and is strongly reduced in presence of a cytosine, in line with the different drug stabilization properties of the two systems. Such a difference is strictly

SUBMITTER: Coletta A 

PROVIDER: S-EPMC3905883 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature