Allostery in the dengue virus NS3 helicase: Insights into the NTPase cycle from molecular simulations

McCullagh, Martin; Davidson, Russell; Hendrix, Josie; Geiss, Brian

Allostery in the dengue virus NS3 helicase: Insights into the NTPase cycle from molecular simulations

dc.contributor.author	McCullagh, Martin
dc.contributor.author	Davidson, Russell
dc.contributor.author	Hendrix, Josie
dc.contributor.author	Geiss, Brian
dc.date.accessioned	2018-03-30T15:43:27Z
dc.date.available	2018-03-30T15:43:27Z
dc.date.issued	2018-03-01
dc.description	Department of Chemistry
dc.description.abstract	The C-terminus domain of non-structural 3 (NS3) protein of the Flaviviridae viruses (e.g. HCV, dengue, West Nile, Zika) is a nucleotide triphosphatase (NTPase) -dependent superfamily 2 (SF2) helicase that unwinds double-stranded RNA while translocating along the nucleic polymer. Due to these functions, NS3 is an important target for antiviral development yet the biophysics of this enzyme are poorly understood. Microsecond-long molecular dynamic simulations of the dengue NS3 helicase domain are reported from which allosteric effects of RNA and NTPase substrates are observed. The presence of a bound single-stranded RNA catalytically enhances the phosphate hydrolysis reaction by affecting the dynamics and positioning of waters within the hydrolysis active site. Coupled with results from the simulations, electronic structure calculations of the reaction are used to quantify this enhancement to be a 150-fold increase, in qualitative agreement with the experimental enhancement factor of 10-100. Additionally, protein-RNA interactions exhibit NTPase substrate-induced allostery, where the presence of a nucleotide (e.g. ATP or ADP) structurally perturbs residues in direct contact with the phosphodiester backbone of the RNA. Residue-residue network analyses highlight pathways of short ranged interactions that connect the two active sites. These analyses identify motif V as a highly connected region of protein structure through which energy released from either active site is hypothesized to move, thereby inducing the observed allosteric effects. These results lay the foundation for the design of novel allosteric inhibitors of NS3.	en_US
dc.format.medium	ZIP
dc.format.medium	TXT
dc.format.medium	AMBER
dc.identifier.uri	https://hdl.handle.net/10217/186709
dc.identifier.uri	https://dx.doi.org/10.25675/10217/186709
dc.language	English
dc.language.iso	eng
dc.publisher	Colorado State University. Libraries	en_US
dc.relation.ispartof	Research Data
dc.relation.isreferencedby	Davidson RB, Hendrix J, Geiss BJ, McCullagh M (2018) Allostery in the dengue virus NS3 helicase: Insights into the NTPase cycle from molecular simulations. PLoS Comput Biol 14(4): e1006103. https://doi.org/10.1371/journal.pcbi.1006103
dc.subject	dengue virus
dc.subject	helicase
dc.subject	allostery
dc.subject	ATP hydrolysis
dc.subject	molecular dynamics
dc.title	Allostery in the dengue virus NS3 helicase: Insights into the NTPase cycle from molecular simulations	en_US
dc.type	Dataset	en_US