Nucleotide-dependent dynamics of the Dengue NS3 helicase

SARTO, CAROLINA; KAUFMAN, SERGIO B.; ESTRIN, DARIO A.; ARRAR, MEHRNOOSH

BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS

ELSEVIER SCIENCE BV

Año: 2020 vol. 1868

1570-9639

Dengue represents a substantial public health burden, particularly in low-resource countries. Non-structuralprotein 3 (NS3) is a multifunctional protein critical in the virus life cycle and has been identified as a promising anti-viral drug target. Despite recent crystallographic studies of the NS3 helicase domain, only subtle structural nucleotide-dependent differences have been identified, such that its coupled ATPase and helicase activities re- main mechanistically unclear. Here we use molecular dynamics simulations to explore the nucleotide-dependent conformational landscape of the Dengue virus NS3 helicase and identify substantial changes in the protein flexibility during the ATP hydrolysis cycle. We relate these changes to the RNA-protein interactions and pro- posed translocation models for other monomeric helicases. Furthermore, we report a novel open-loop con- formation with a likely escape route for Pi after hydrolysis, providing new insight into the conformational changes that underlie the ATPase activity of NS3.