Three-State Diffusion Model of DNA Glycosylase Translocation along Stretched DNA as Revealed by Free Energy Landscapes at the All-Atom Level

Abstract

DNA glycosylases play key roles in the maintenance of genomic integrity. These enzymes effectively find rare damaged sites in DNA and participate in subsequent base excision repair. Single-molecule and ensemble experiments have revealed key aspects of this damage-site searching mechanism and the involvement of facilitated diffusion. In this study, we describe free energy landscapes of enzyme translocation along nonspecific DNA obtained using a fully atomistic molecular dynamics (MD) simulation of a well-known DNA glycosylase, human 8-oxoguanine DNA glycosylase 1 (hOGG1). Based on an analysis of simulated free energy profiles, we propose a three-state model for the damage-site searching mechanism. In the three states, named the L1, L2, and L3 states, the L1 state is a helical sliding mode in close contact with DNA, whereas the L2 state is a major-or minor-groove tracking mode in loose contact with DNA and the L3 state is a two-dimensional freely diffusing mode during which hOGG1 is somewhat removed from the DNA surface (∼24 Å away from the surface). This three-state model well describes key experimental findings obtained from single-molecule and ensemble experiments and provides a unified molecular picture of the DNA lesion-searching mechanism of hOGG1.