Rapid spread of ZIKA virus (ZIKV) and its association with severe birth defects have raised worldwide concern. Currently, there are no specific drugs or vaccines available against Zika infection. However, the drug designing strategies rely upon the thorough understanding of the structure and dynamics of various structural and functional proteins of the virus. Recent studies have shown that ZIKV retains its infectivity and remains structurally stable at temperatures up to 40 °C, unlike dengue virus (DENV). In this thesis we attempted to understand the molecular basis of greater thermal stability of ZIKV over DENV2 at critical physiological conditions, such as high fever. Our results suggest that the ZIKA E-protein shell retains its structural integrity through stronger inter-raft communications, facilitated by a network of electrostatic and H-bonding interactions in comparison to the weak hydrophobic interactions on DENV2 glycoprotein shell surface. Subsequently, through coarse-grained molecular dynamics simulations and computational mutagenesis studies, we found that the DIII domain, more specifically, the CD- and FG-loop residues of ZIKV glycoprotein shell play a crucial role in making the virus envelope thermostable by inducing strong raft-raft interactions via multiple electrostatic and H-bonds. Besides exploring the structural envelope protein of ZIKV, we also investigated a key functional protein - the NS3 protease, a key enzyme in viral maturation. Here, we attempted to understand the role of NS2B cofactor in the structural stability and activity of NS3 protease. Results from the Gaussian accelerated MD simulations of ZIKA protease revealed that the binding of NS2B cofactor helps in retaining the key secondary structural elements in the active site region and thus helps NS3 protease to maintain its native fold. Our substrate binding studies showed that the NS2B cofactor facilitates substrate binding not only by directly interacting with the N-terminal substrate residues, but also by providing electrostatic complementarity in the active site. The details obtained from our study could pave the way for designing small molecule inhibitors and specific antibodies against Zika virus.

Publications:
1. Chinmai Pindi, Venkat R Chirasani and Sanjib Senapati, “Identifying crucial E-protein residues responsible for greater thermostability of Zika virus over Dengue”, Biophysical Journal, 2021, 120 (18):4041.

2. Chinmai Pindi, Venkat R. Chirasani, Homaidur Rahman, Mohd Ahsan, Prasanna D. Revanasiddappa and Sanjib Senapati, “Molecular Basis of Differential Stability and Temperature Sensitivity of ZIKA versus Dengue Virus Protein Shells”, Scientific Reports, 2020, 10(1):8411.