Contact networks encode the ATP-induced dynamic structural asymmetry of condensin head domains

Abstract

Condensin, a structural maintenance of chromosomes (SMC) complex, plays a central role in genome organization by driving DNA loop extrusion through ATP hydrolysis. Experimental studies have revealed an asymmetric ATP-binding order at the Smc4- and Smc2-linked head domains, but the molecular origin and temperature dependence of this asymmetry remain poorly understood. Here, we combine coarse-grained switching-Gō models with all-atom molecular dynamics simulations to investigate how contact-network architecture in ATP-like states governs the order and thermal sensitivity of ATP-competent pocket formation. We find that the Smc4-associated ATP pocket (ATP1) exhibits higher local contact density and greater thermal stability than the Smc2-associated pocket (ATP2), favoring initial ATP1 pocket formation. As temperature increases, the formation of ATP2-binding-competent conformations becomes increasingly dependent on prior ATP1 pocket organization. Contact-network analysis of ATP-induced conformational transitions identifies specific structural regions that mediate this thermodynamic shift, revealing a temperature-dependent shift from independent to sequential pocket formation, consistent with the experimentally observed ATP-binding order at the two head sites. All-atom simulations provide supporting evidence that ATP1 pockets are highly persistent when the nucleotide is present but destabilize upon removal, whereas ATP2 pockets show greater intrinsic pre-organization in the ATP-absent state yet are less persistent when bound than ATP1 pockets. Together, these results advance a thermodynamic framework showing how contact-network connectivity encodes asymmetric, temperature-sensitive conformational competence for nucleotide engagement in condensin.