Free energy calculations reveal rotating-ratchet mechanism for DNA supercoil relaxation by topoisomerase IB and its inhibition.

ABSTRACT: Topoisomerases maintain the proper topological state of DNA. Human topoisomerase I removes DNA supercoils by clamping a duplex DNA segment, nicking one strand at a phosphodiester bond, covalently attaching to the 3' end of the nick, and allowing the DNA downstream of the cut to rotate around the intact strand. Using molecular dynamics simulations and umbrella sampling free energy calculations, we show that the rotation of downstream DNA in the grip of the enzyme that brings about release of positive or negative supercoils occurs by thermally assisted diffusion on ratchet energy profiles. The ratchetlike free-energy-versus-rotation profile that we compute provides a model for the function of topoisomerase in which the periodic maxima along the profile modulate the rate of supercoil relaxati

SUBMITTER: Wereszczynski J 

PROVIDER: S-EPMC2913206 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature