Chromatin remodelers couple inchworm motion with twist-defect formation to slide nucleosomal DNA

Abstract

ATP-dependent chromatin remodelers control genome organization by repositioning, ejecting, or editing nucleosomes, activities that confer them essential regulatory roles on gene expression and DNA replication. Here, we investigate the mechanism of active DNA sliding by remodelers, which underlies most remodeling functions, via molecular dynamics simulations of the Snf2 remodeler in complex with a nucleosome. During its inchworm motion driven by ATP consumption, the remodeler overwrites the original nucleosome energy landscape via steric and electrostatic interactions to induce sliding of nucleosomal DNA. Repositioning is initiated at the remodeler binding location via the generation of twist defects, which then spontaneously propagate to complete sliding throughout the entire nucleosome. We also reveal how remodeler mutations and DNA sequence control active nucleosome repositioning. These results offer a mechanistic understanding of chromatin remodeling important for the interpretation of experimental studies.