Delving into Zika virus structural dynamics – a closer look at NS3 helicase loop flexibility and its role in drug discovery

Abstract

The Zika virus has emerged as a pathogen of major health concern. The rapid spread of the virus has led to uproar in the medical domain as scientists frantically race to develop effective vaccines and small molecules to inhibit the virus. In the past year, there has been a flood of Zika knowledge published including its characteristics, transmission routes and its role in disease conditions such as microcephaly and Gullian–Barŕe syndrome. Targeted therapy against specific viral maturation proteins is necessary in halting the replication of the virus in the human host, thus decreasing host–host transmission. This prompted us to investigate the structural properties of the Zika NS3 helicase when bound to ATP-competitive inhibitor, NITD008. In this study, comparative molecular dynamic simulations were employed for APO and bound protein to demonstrate the molecular mechanism of the helicase. Results clearly revealed that NITD008-binding caused significant residue fluctuations at the P-loop compared to the rigid nature of the APO conformation. The NITD008-helicase complex also revealed residues 339–348 to transition from a ₃10-helix to a stable α-helix. These protein fluctuations were verified by investigation of dynamic cross correlation and principal component analysis. The fundamental dynamic analysis presented in this report is crucial in understanding Zika NS3 helicase function, thereby giving insights toward an inhibition mechanism. The information reported on the binding mode at the ATPase active site may also assist in designing effective inhibitors against this detrimental viral target.