Molecular dynamics simulations of Zika virus NS3 helicase: Insights into RNA binding site activity.
America is still suffering with the outbreak of Zika virus (ZIKV) infection. Congenital ZIKV syndrome has already caused a public health emergency of international concern. However, there are still no vaccines to prevent or drugs to treat the infection caused by ZIKV. The ZIKV NS3 helicase (NS3h) protein is a promising target for drug discovery due to its essential role in viral genome replication. NS3h unwinds the viral RNA to enable the replication of the viral genome by the NS5 protein. NS3h contains two important binding sites: the NTPase binding site and the RNA binding site. Here, we used molecular dynamics (MD) simulations to study the molecular behavior of ZIKV NS3h in the presence and absence of ssRNA and the potential implications for NS3h activity and inhibition. Although there is conformational variability and poor electron densities of the RNA binding loop in various apo flaviviruses NS3h crystallographic structures, the MD trajectories of NS3h-ssRNA demonstrated that the RNA binding loop becomes more stable when NS3h is occupied by RNA. Our results suggest that the presence of RNA generates important interactions with the RNA binding loop, and these interactions stabilize the loop sufficiently that it remains in a closed conformation. This closed conformation likely keeps the ssRNA bound to the protein for a sufficient duration to enable the unwinding/replication activities of NS3h to occur. In addition, conformational changes of this RNA binding loop can change the nature and location of the optimal ligand binding site, according to ligand binding site prediction results. These are important findings to help guide the design and discovery of new inhibitors of NS3h as promising compounds to treat the ZIKV infection.
LabMol, Faculty of Pharmacy, Universidade Federal de Goias, Goiânia, GO, 74605-170, Brazil.
Melina
M
Mottin
LabMol, Faculty of Pharmacy, Universidade Federal de Goias, Goiânia, GO, 74605-170, Brazil.
Rodolpho C
RC
Braga
NCBios, Universidade Federal de Goias, Jatai, GO, 74605-170, Brazil.
Roosevelt A
RA
da Silva
Fiocruz Ceará - Fundação Oswaldo Cruz, Fortaleza, CE, Brazil.
Joao H Martins da
JHMD
Silva
Department of Pharmacology, Physiology and Neuroscience, Rutgers University-New Jersey Medical School, Newark, NJ, 07103, United States.
Alexander L
AL
Perryman
Collaborations Pharmaceuticals, Inc., 5616 Hilltop Needmore Road, Fuquay-Varina, NC, 27526, United States.
Sean
S
Ekins
LabMol, Faculty of Pharmacy, Universidade Federal de Goias, Goiânia, GO, 74605-170, Brazil. Electronic address: carolhandrade@gmail.com.
Carolina Horta
CH
Andrade
D001665:Binding Sites; D004789:Enzyme Activation; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D011487:Protein Conformation; D020365:RNA Helicases / Q000737:chemistry / Q000648:ultrastructure; D012367:RNA, Viral / Q000737:chemistry* / Q000648:ultrastructure*; D012697:Serine Endopeptidases / Q000737:chemistry / Q000648:ultrastructure; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000648:ultrastructure*; D000071244:Zika Virus / Q000201:enzymology*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D020365:RNA Helicases; D012367:RNA, Viral; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
Drug discovery; FTMap; Flavivirus; Molecular dynamics; NS3 helicase; Zika virus