Nucleotide-dependent dynamics of the Dengue NS3 helicase

ESTRIN, DARÍO ARIEL; SARTO, CAROLINA; DI LELLA, SANTIAGO; KAUFMAN, SERGIO; ARRAR, MEHRNOOSH

San Luis

Congreso; XLVIII Reunión Anual de la Sociedad Argentina de Biofísica; 2019

Sociedad Argentina de Biofísica

Dengue represents a substantial public health burden, particularly in low-resource countries. Non-structural protein 3 is a multifunctional protein critical in the virus life cycle that has been identified as a promising anti-viral drug target. Despite recent crystallographic studies of the DENV NS3 helicase domain (NS3hel), no structural nucleotide-dependent differences have been identified, such that the coupled ATPase and helicase activities of the NS3hel remain mechanistically unclear. Here we use molecular dynamics simulations to explore the nucleotide-dependent conformational landscape of the DENV NS3 helicase and identify substantial changes in the protein flexibility during the ATP hydrolysis cycle. We relate these changes, including a novelopen-loop conformation in the absence of ATP, to the specific RNA-protein interactions and proposed translocation models for other monomeric helicases.