SMC complex unidirectionally translocates DNA by coupling segment capture with an asymmetric kleisin path

ABSTRACT SMC (structural maintenance of chromosomes) protein complexes are ring-shaped molecular motors essential for genome folding. Despite recent progress, the detailed molecular mechanism of DNA translocation in concert with the ATP-driven conformational changes of the complex remains to be clarified. In this study, we elucidated the mechanisms of SMC action on DNA using multiscale molecular dynamics simulations. We first created a near-atomic full-length model of prokaryotic SMC-kleisin complex that implemented protein-DNA hydrogen bond interactions derived from fully atomistic simulations and emulated ATP-dependent conformational changes. Extensive simulations of the SMC complex with 800 base pairs of duplex DNA over the ATP cycle revealed unidirectional DNA translocation via the DNA segment capture mechanism. The process exhibited a step size of ∼200 base pairs, wherein the complex captured a DNA segment of about the same size within the SMC ring in the engaged state, followed by its pumping into the kleisin ring as ATP was hydrolyzed. We found that the hinge-DNA interaction is not critical for the DNA translocation. On the other hand, analysis of trajectories identified the asymmetric path of the kleisin as a critical factor for the observed unidirectionality. SIGNIFICANCE STATEMENT Ring-shaped SMC (structural maintenance of chromosomes) protein complexes, which are highly conserved across all three domains of life, play an essential role in chromosome organization through a process called DNA loop extrusion. However, the molecular mechanism underlying the ATP-dependent motor activity of SMC complexes remains unclear. Using all-atom and residue-resolution coarse-grained molecular dynamics simulations, we revealed that prokaryotic SMC complexes translocate unidirectionally along DNA via a segment capture mechanism. We found that the unidirectionality arises from the kleisin subunit breaking the symmetry of the ring-shaped SMC complex structure. Our findings provide insights into the molecular motor mechanisms shared by SMC complexes.