The methyltransferase (MTase) domain of non-structural protein 5 (NS5) plays a fundamental role in flaviviruses replication, and its inhibition is a strategy for antiviral development. MTase methylates viral RNA cap at guanine N-7 and the ribose 2'OH of the first adenosine. Many structures of Zika virus (ZIKV) and other flaviviruses MTases bound to cofactors, substrates and inhibitor candidates have been solved. Still, the dynamical modulation of MTase binding and catalytic activity yet needs to be clarified. Here, we investigated the structural dynamics of ZIKV NS5 MTase domain free and bound to Guanosine-5'-triphosphate (GTP) and S-Adenosyl-Lmethionine (SAM), to identify the molecular dynamics changes related to ligand binding and methyl transfer reaction. We have observed that the binding of the GTP and SAM individually and GTP-SAM in the ternary complex has induced allostery in the RNA binding site, showing the complexity of ZIKV MTase conformational equilibrium and its impact on viral RNA recognition. We also mapped in molecular dynamics trajectories, conformations of GTP guanine moiety that mimics guanine orientations visualized in human-specific N-methyltransferase structures solved by X-ray crystallography. It is the first time that N-7 methylation-prone guanine orientation has been proposed and modeled in flavivirus MTase. Communicated by Ramaswamy H. Sarma.
Keywords: RNA methylation; Zika virus; methyltransferase; molecular dynamics; non-structural protein 5.