Conformational Changes and ATP Hydrolysis in Zika Helicase. The Molecular Basis of a Biomolecular Motor Unveiled by Multiscale Simulations

We computationally study Zika NS3 helicase, a biological motor using ATP hydrolysis energy for nucleic acid remodelling. Through classical and QM/MM simulations, we explore the conformational landscape of Motif V, a conserved loop connecting the active sites for ATP hydrolysis and nucleic acid binding. ATP hydrolysis, initiated by a meta-phosphate group formation, involves the nucleophilic attack of a water molecule activated by Glu286 proton abstraction. Motif V hydrogen bonds to this water via Gly415 backbone NH group, assisting hydrolysis. Post-hydrolysis, free energy is released when the inorganic phosphate moves away from the coordination shell of the magnesium ion, inducing a significant shift in the conformational landscape of Motif V to establish a hydrogen bond between Gly415 NH and Glu285. Zika NS3 helicase acts as a ratchet biological motor with Motif V transitions steered by Gly415’s γ-phosphate sensing in the ATPase site.